Introduction
Chemoresistance remains a major obstacle in cancer therapy, contributing to treatment failure, tumour recurrence, metastasis and poor clinical outcomes (Ref. Reference Longley and Johnston1). It develops through intrinsic or acquired mechanisms that enable cancer cells to evade chemotherapy-induced cytotoxicity (Ref. Reference Zheng2). These include altered drug metabolism by cytochrome P450 enzymes (Refs Reference Altenberg3, Reference Doyle, Yang, Abruzzo, Krogmann, Gao, Rishi and Ross4), enhanced DNA repair mediated by BRCA1/2 and PARP (Ref. Reference Kachalaki, Ebrahimi, Mohamed Khosroshahi, Mohammadinejad and Baradaran5), resistance to apoptosis through dysregulated BCL-2 and TP53 (Refs Reference Abdel-Fatah, Perry, Dickinson, Ball, Moseley, Madhusudan, Ellis and Chan6, Reference Masciarelli, Fontemaggi, di Agostino, Donzelli, Carcarino, Strano and Blandino7) and epithelial–mesenchymal transition (EMT), which promotes stem cell-like properties and therapeutic resistance. Key genes, including MDR1, ABCB1, TP53, BRCA1/2, BCL-2 and STAT3, further facilitate drug efflux, DNA repair and survival signalling, allowing resistant clones to emerge under therapeutic pressure (Refs Reference Zheng2, Reference Abdullah and Chow8).
Beyond these established mechanisms, increasing evidence implicates mitochondrial homeostasis in therapeutic resistance. Mitochondrial dynamics including fission, fusion, biogenesis and mitophagy regulate cellular metabolism, bioenergetics and apoptosis and their dysregulation promotes metabolic adaptation and cancer cell survival following chemotherapy (Ref. Reference Bahar, Han, Kim and Yoon9). Although alterations in mitochondrial dynamics have been increasingly associated with chemoresistance (Refs Reference Longley and Johnston1, Reference Ramos, Sadeghi and Tabatabaeian10), the underlying molecular mechanisms remain incompletely understood, highlighting the need to identify novel therapeutic targets (Ref. Reference Wang, Liu, Cao, Zhang, Huang and Yi11).
Among the proteins involved in mitochondrial homeostasis, Stomatin-like protein 2 (STOML2) has emerged as a promising candidate that may contribute to mitochondrial remodelling and therapeutic resistance in cancer. STOML2 belongs to the mammalian stomatin protein family, which comprises protostomatin, STOML1, STOML2, STOML3 and podocin. Unlike other family members, STOML2 is predominantly localised to the inner mitochondrial membrane (IMM), where it has been implicated in maintaining mitochondrial integrity, regulating bioenergetics and coordinating multiple aspects of mitochondrial dynamics (Ref. Reference Kulikov, Luchkina, Gogvadze and Zhivotovsky12). Growing evidence from experimental and clinical studies suggests that aberrant STOML2 expression is associated with aggressive tumour behaviour, poor prognosis and reduced therapeutic response across several malignancies. However, the functional significance of STOML2 appears to vary depending on tumour type and experimental context, indicating that its precise biological role has yet to be fully established.
Recent studies have suggested that STOML2 may influence mitochondrial quality control through interactions with proteins involved in the mitophagy pathway, particularly PTEN-induced kinase 1 (PINK1) and the mitochondrial rhomboid protease PARL (Refs Reference Gong, Chen, Liu, Hu, Li, Li, Li, Huang, Li and Fang13, Reference Qin, Wang, Zhao, Li, Li, Yang, Zhao and Wang14, Reference De Rasmo, Cormio, Cormio and Signorile15). Under physiological conditions, PINK1 is constitutively imported into healthy mitochondria, where it undergoes PARL-mediated cleavage and subsequent degradation, thereby preventing unnecessary activation of mitophagy. Mitochondrial damage disrupts this process, resulting in PINK1 accumulation on the outer mitochondrial membrane (OMM) and recruitment of the E3 ubiquitin ligase Parkin, which initiates selective removal of dysfunctional mitochondria. Experimental evidence suggests that STOML2 may modulate this pathway through its interaction with PARL and other mitochondrial membrane proteins; however, the precise molecular mechanisms underlying these interactions remain incompletely understood and may differ depending on the cellular context (Refs Reference Gong, Chen, Liu, Hu, Li, Li, Li, Huang, Li and Fang13, Reference Qin, Wang, Zhao, Li, Li, Yang, Zhao and Wang14, Reference De Rasmo, Cormio, Cormio and Signorile15). Consequently, although increasing evidence links STOML2 to mitochondrial quality control and chemoresistance, many of the proposed mechanistic relationships remain to be validated in clinically relevant models.
In addition to its proposed role in mitophagy, STOML2 has been associated with several signalling pathways implicated in tumour progression, including NF-κB, MAPK/ERK, IL6–JAK/STAT3 and mitochondrial apoptotic signalling (Refs Reference De Rasmo, Cormio, Cormio and Signorile15, Reference Ma, Chen, Xiong, Li, Xu, Wang, Wei, Mou, Wu, Cheng, Zou, Zhu, Zhou, Liu and Geng16). Current evidence suggests that STOML2 may influence these pathways either directly or indirectly through its effects on mitochondrial function, cellular metabolism and oxidative stress. However, the extent to which these signalling networks are directly regulated by STOML2, rather than representing downstream or context-dependent consequences of mitochondrial dysfunction, remains an area of active investigation. Therefore, caution should be exercised when interpreting these interactions as universally conserved mechanisms across different cancer types.
Cancer cells undergo extensive mitochondrial remodelling to satisfy the increased bioenergetic and biosynthetic demands associated with rapid proliferation and adaptation to therapeutic stress (Refs Reference Lapatsina, Brand, Poole, Daumke and Lewin17, Reference Dey and Ganguly18). Within this context, STOML2 has been reported to contribute to the maintenance of mitochondrial function by supporting mitochondrial fusion, respiratory chain organisation and mitochondrial biogenesis, thereby facilitating cellular adaptation under stressful conditions (Ref. Reference Lapatsina, Brand, Poole, Daumke and Lewin17). Nevertheless, much of the available evidence has been generated using in vitro cell culture systems and gene-silencing approaches, whereas comprehensive in vivo validation and clinical investigations remain comparatively limited. Consequently, although STOML2 represents a promising therapeutic candidate, additional studies are required to establish whether its inhibition can produce clinically meaningful anti-tumour responses while minimising potential toxicity to normal tissues.
The growing recognition of STOML2 as a potential therapeutic target has also stimulated interest in computational drug discovery approaches, including structure-based virtual screening and rational drug design. However, the successful application of these strategies remains challenging because the three-dimensional structure, oligomeric organisation and dynamic conformational properties of STOML2 have not yet been fully elucidated. This limited structural knowledge restricts the identification of druggable binding pockets, hinders structure-guided inhibitor development and complicates efforts to selectively target STOML2 while preserving normal mitochondrial function. Consequently, further structural characterisation using advanced computational modelling and experimental techniques will be essential for facilitating future therapeutic development.
Recent work by Dey and colleagues (Ref. Reference Dey and Ganguly18) has highlighted that stomatin and stomatin-like proteins (SLPs) constitute a highly conserved protein family involved in regulating membrane-associated proteins, maintaining membrane integrity, organising lipid raft microdomains and interacting with ion channels and membrane transporters. These functions indirectly influence multiple cellular processes that support cancer cell survival, proliferation, migration and metastasis, suggesting that dysregulated expression of SLP family members, rather than the proteins themselves, may contribute to tumour progression. Collectively, these findings emphasise the biological importance of STOML2 while also underscoring the need for a more comprehensive understanding of its structural organisation, molecular interactions and context-dependent functions in cancer biology.
Despite the rapidly expanding body of literature linking STOML2 with mitochondrial dynamics, tumour progression and therapeutic resistance, several important questions remain unresolved. Most mechanistic evidence has been derived from in vitro studies and experimental gene-silencing approaches, whereas comparatively fewer investigations have validated these findings in animal models or large clinical cohorts. Furthermore, the precise structural organisation of STOML2, the mechanisms governing its interactions with mitochondrial quality-control pathways and its potential as a clinically actionable therapeutic target remain incompletely understood. These limitations highlight the need for a critical evaluation of the available evidence rather than solely a descriptive summary of published findings.
Therefore, this review critically examines the current understanding of STOML2 biology by integrating evidence related to its structural characteristics, mitochondrial functions, signalling pathways and involvement in tumour progression and chemoresistance. In addition to summarising recent advances, this review evaluates the strengths and limitations of existing studies, distinguishes experimentally validated mechanisms from emerging hypotheses, discusses tumour-specific and context-dependent observations and highlights key knowledge gaps that should guide future research. By providing a balanced assessment of the available literature, we aim to clarify the current therapeutic potential of STOML2 and identify priorities for its future clinical translation.
Literature search strategy
This narrative review was conducted using a structured literature search to improve methodological transparency and minimise selection bias. Publications published between 2010 and 2025 were identified through PubMed, Scopus and Google Scholar using combinations of the keywords ‘STOML2,’ ‘stomatin-like protein 2,’ ‘mitochondrial dynamics,’ ‘mitochondria,’ ‘mitophagy,’ ‘chemoresistance,’ ‘therapy,’ ‘cancer’ and ‘cancer signalling pathways.’ Boolean operators (AND/OR) were applied where appropriate to refine the search strategy. Only peer-reviewed articles published in English that investigated STOML2 in relation to tumour biology, mitochondrial function, mitochondrial quality control, chemoresistance or therapeutic response were considered for inclusion. Review articles were additionally consulted to provide background information and identify relevant primary studies. Greater emphasis was placed on recent mechanistic, translational and clinical investigations published within the last five years to ensure that the review reflects current advances while also incorporating seminal earlier studies that established the biological role of STOML2.
Structure of STOML2
STOML2 belongs to the stomatin protein family and contains the highly conserved stomatin/prohibitin/flotillin/HflK-HflC (SPFH) domain (Ref. Reference Gonzalez-Velandia, Hernandez-Clavijo, Menini, Dibattista and Pifferi19). The SPFH domain represents a characteristic structural motif shared among several evolutionarily conserved protein families, including stomatins, flotillins, prohibitins (PHBs) and HflK/HflC proteins, where it primarily functions as a membrane-associated scaffold involved in protein complex assembly and membrane organisation. Approximately 1,300 proteins within annotated databases are predicted to contain a detectable SPFH domain (Ref. Reference Ma, Wang, Luo, Yan, Yang, Li and Gao20). Phylogenetic analyses have demonstrated that stomatin-domain proteins form a distinct evolutionary branch within the SPFH superfamily, separating early from other eukaryotic SPFH proteins such as flotillins and PHBs (Ref. Reference Tavernarakis, Driscoll and Kyrpides21). Within STOML2, the SPFH domain is believed to facilitate homo-oligomerisation and the formation of specialised membrane microdomains (lipid rafts), thereby contributing to mitochondrial membrane organisation and protein complex stabilisation. The N-terminal region is involved in membrane association and protein–protein interactions, whereas the C-terminal region has been proposed to participate in mechanosensory signalling, intracellular trafficking and cytoskeletal interactions (Ref. Reference Morrow and Parton22). However, the precise structural basis underlying these functions remains incompletely characterised owing to the absence of an experimentally resolved full-length STOML2 structure.
Current structural knowledge of the SPFH domain is largely derived from X-ray crystallographic studies of archaeal stomatin homologues rather than human STOML2 itself. These studies identified a trimeric structural arrangement suggesting that homo-oligomerisation may be mediated by interactions involving the C-terminal α-helices (Ref. Reference Morrow and Parton22). Although members of the stomatin family share approximately 40–84% sequence similarity within the conserved stomatin domain, STOML2 exhibits a unique membrane organisation and domain architecture compared with other stomatin family proteins (Ref. Reference Rivera-Milla, Stuermer and Málaga-Trillo23). Specifically, STOML2 contains a conserved SPFH core domain together with a short hydrophobic insertion region harbouring a proline residue that is predicted to facilitate the formation of a hairpin-like conformation within the monomeric protein (Ref. Reference Ma, Chen, Xiong, Li, Xu, Wang, Wei, Mou, Wu, Cheng, Zou, Zhu, Zhou, Liu and Geng16). Furthermore, despite sharing conserved intracellular N- and C-terminal orientations with other stomatin family members (Refs Reference Yokoyama, Fujii and Matsui24, Reference Green and Young25), STOML2 lacks the characteristic hydrophobic N-terminal transmembrane anchor that is present in most other stomatin proteins (Ref. Reference Snyers, Umlauf and Prohaska26). This distinctive structural feature is thought to contribute to its unique intracellular localisation and functional specialisation.
The absence of a classical hydrophobic N-terminal membrane anchor enables STOML2 to localise predominantly to the IMM while also being detected in other membrane compartments under specific cellular conditions. Within mitochondria, STOML2 has been reported to interact with cardiolipin, an IMM-specific phospholipid, thereby contributing to the maintenance of mitochondrial membrane potential, respiratory chain organisation and overall mitochondrial stability. Interactions with additional mitochondrial proteins are also believed to support its role in maintaining mitochondrial architecture and regulating mitochondrial function, although the molecular mechanisms governing these interactions remain incompletely understood (Ref. Reference Owczarek, Treutlein, Portbury, Gulluyan, Kola and Hertzog27). Human STOML2 consists of 356 amino acids with an approximate molecular weight of 38.5 kDa (Ref. Reference Green and Young25).
Several structurally distinct regions have been identified within STOML2 (Figure 1A,B). The mitochondrial targeting sequence is located within the intrinsically disordered N-terminal region (residues 1–28) (Refs Reference Snyers, Umlauf and Prohaska26, Reference Owczarek, Treutlein, Portbury, Gulluyan, Kola and Hertzog27). The conserved SPFH domain comprises an N-terminal α/β region followed by two structurally distinct subdomains. SPFH1 (residues 38–78) contains five β-sheets, whereas SPFH2 (residues 82–181) consists of four α-helices and three β-sheets (Figure 1A,B). The C-terminal region includes three α-helical segments α1 (184–265), α2 (270–292) and α3 (305–321) followed by an intrinsically disordered region spanning residues 322–356 (Refs Reference Snyers, Umlauf and Prohaska26, Reference Owczarek, Treutlein, Portbury, Gulluyan, Kola and Hertzog27). These α-helical regions are proposed to contribute to protein oligomerisation and membrane-associated protein interactions; however, direct experimental validation of these structural roles remains limited.
A. Schematic representation of the domain architecture of STOML2, highlighting its N-terminal SPFH1 and SPFH2 domains followed by three C-terminal α-helical regions (α1–α3). B. Predicted 3D structural model illustrating the spatial arrangement of SPFH domains and α-helical segments, showing how these features may contribute to STOML2ʼs membrane-associated conformation. C. Proposed localisation and functional interactions of STOML2 within the IMM. STOML2 is shown interfacing with key mitochondrial dynamics regulators, including Mfn2 on the OMM and OPA1/OMA1 within the IMS, as well as with prohibitin complexes (PHB1/PHB2).
Figure 1. Long description
Panel A is a linear domain map of S T O M L 2 from amino acid 1 at the N-terminus to 356 at the C-terminus. It features a green S P F H 1 domain, an orange S P F H 2 domain, and three blue alpha-helical regions labeled alpha 1, alpha 2, and alpha 3.
Panel B is a 3D ribbon model. On the left, dark blue globular structures represent S P F H 1 and S P F H 2. Extending to the right is a long blue alpha 1 helix, followed by a folded alpha 2 helix and a yellow alpha 3 helix at the distal end.
Panel C is a cross-section of the mitochondria showing the O M M, I M S, I M M, and Matrix.
• At the top left, an orange S T O M L 2 protein in the I M M interacts across the I M S with a teal M f n 2 protein on the O M M, marked with a plus sign.
• Moving down a cristae fold, S T O M L 2 interacts with a green O M A 1 and a purple O P A 1 protein, marked with minus signs.
• At the bottom right, a box labeled ELECTRON TRANSPORT CHAIN contains complexes Roman numeral 1, 3, 4, and A T P Synthase. A T P Synthase converts A D P to A T P. A dashed arrow connects the T C A Cycle to the chain.
• At the top right, S T O M L 2 is shown adjacent to a Prohibitin complex consisting of blue Prohibitin 1 and purple Prohibitin 2.
Recent advances in artificial intelligence (AI)-based protein structure prediction have provided additional insights into the structural organisation of STOML2 despite the absence of an experimentally resolved full-length structure. Computational models generated using platforms such as AlphaFold have predicted a well-defined SPFH core domain together with highly ordered C-terminal α-helical regions, whereas the N-terminal mitochondrial targeting sequence and terminal-disordered segments exhibit comparatively lower confidence scores, consistent with their intrinsically flexible nature (Ref. Reference Varadi, Anyango, Deshpande, Nair, Natassia, Yordanova, Yuan, Stroe, Wood, Laydon, Žídek, Green, Tunyasuvunakool, Petersen, Jumper, Clancy, Green, Vora, Lutfi, Figurnov, Cowie, Hobbs, Kohli, Kleywegt, Birney, Hassabis and Velankar28). These predicted structures provide a valuable framework for identifying putative oligomerisation interfaces, protein–protein interaction surfaces and potential ligand-binding pockets that may facilitate future structure-guided drug discovery. However, it is important to recognise that these computational models remain predictive rather than experimentally validated and may not accurately capture conformational flexibility, oligomeric assembly, membrane interactions or dynamic structural rearrangements that occur under physiological conditions. Therefore, high-resolution experimental approaches such as cryogenic electron microscopy, X-ray crystallography or nuclear magnetic resonance spectroscopy remain essential for validating the structural organisation of STOML2 and enabling the rational design of selective therapeutic inhibitors.
Evolutionary analyses indicate that STOML2 diverged early from other members of the eukaryotic stomatin family despite retaining strong conservation within its SPFH core domain. Like other stomatin family proteins, STOML2 is expressed in adult erythrocytes and several metabolically active granular tissues (Refs Reference Green and Young25–Reference Varadi, Anyango, Deshpande, Nair, Natassia, Yordanova, Yuan, Stroe, Wood, Laydon, Žídek, Green, Tunyasuvunakool, Petersen, Jumper, Clancy, Green, Vora, Lutfi, Figurnov, Cowie, Hobbs, Kohli, Kleywegt, Birney, Hassabis and Velankar28). Despite substantial progress in characterising its domain organisation, important structural questions remain unresolved, including its complete three-dimensional architecture, oligomeric organisation, conformational dynamics and the molecular basis of its interactions with mitochondrial proteins. These unresolved structural features currently represent a major limitation for structure-guided drug discovery and the rational design of selective STOML2-targeted therapeutics.
Localisation and functions of STOML2
STOML2 is predominantly localised to the IMM, although it has also been detected in membrane rafts, the mitochondrial intermembrane space (IMS), and, under certain experimental conditions, at the plasma membrane (Ref. Reference Liu, Zhang, Shen, Tan, Hu, Yu and Li29). This diverse subcellular distribution suggests that STOML2 performs multiple context-dependent functions extending beyond mitochondrial homeostasis. Membrane rafts serve as specialised membrane microdomains involved in cellular signalling, membrane organisation and protein trafficking, whereas the IMM and IMS are essential for oxidative phosphorylation (OXPHOS), ATP production, mitochondrial protein quality control and intracellular signalling (Ref. Reference Wang and Morrow30). As illustrated in Figure 1C, STOML2 has been reported to associate with the external surface of the plasma membrane, although its predominant localisation within mitochondria has been consistently demonstrated across multiple cell types (Refs Reference Liu, Zhang, Shen, Tan, Hu, Yu and Li29, Reference Wang and Morrow30). Experimental studies further indicate that the N-terminal mitochondrial targeting sequence directs STOML2 to mitochondria, facilitating its import into the IMM (Ref. Reference Morrow and Parton22). Numerous independent studies have subsequently confirmed its mitochondrial localisation using biochemical and imaging approaches (Refs Reference Browman, Hoegg and Robbins31, Reference Zhang, Li, Fu, Adu-Gyamfi, Xu, Liu, Chen, Lan, Wang, Xu and Ding32, Reference Wong, Wagner, Scott, Okreglak, Holewinske, Cassidy-Stone and Nunnari33).
Several studies have suggested that STOML2 possesses GTPase-related activity that contributes to the maintenance of mitochondrial architecture and the regulation of cellular processes including signal transduction, mitochondrial protein synthesis and cell division (Refs Reference Wong, Wagner, Scott, Okreglak, Holewinske, Cassidy-Stone and Nunnari33, Reference Liu, Song, Yan and Liu34). Although the precise molecular basis of this GTPase-associated function remains to be fully elucidated, current evidence indicates that STOML2 supports the activity of mitochondrial fusion proteins and contributes to the maintenance of mitochondrial dynamics rather than functioning as a classical GTPase itself. Additional mechanistic studies are required to determine how this activity influences mitochondrial remodelling under physiological and pathological conditions.
One of the best-characterised functions of STOML2 is its interaction with cardiolipin, a mitochondria-specific phospholipid that plays a fundamental role in maintaining the structural and functional integrity of the IMM (Ref. Reference Christie, Lemke, Elias, Chau, Kirchhof, Li, Ball, Dunn, Hatch and Madrenas35). Through its association with cardiolipin, STOML2 has been reported to contribute to the preservation of mitochondrial membrane potential, respiratory chain organisation and membrane stability. These interactions are also proposed to facilitate inorganic cation transport, maintain mitochondrial ionic homeostasis, regulate calcium efflux and support intracellular calcium buffering, thereby contributing to mitochondrial signalling and overall cellular homeostasis (Refs Reference Demaurex, Poburko and Frieden36, Reference Cruz, De Marchi, Frieden, Parone, Martinou and Demaurex37). Furthermore, experimental evidence suggests that STOML2 positively influences cardiolipin metabolism by promoting its synthesis and appropriate distribution within the IMM, processes that are essential for optimal mitochondrial function (Ref. Reference Christie, Lemke, Elias, Chau, Kirchhof, Li, Ball, Dunn, Hatch and Madrenas35). By preserving mitochondrial membrane integrity, STOML2 has also been associated with enhanced mitochondrial DNA maintenance, mitochondrial biogenesis and cellular bioenergetics (Refs Reference Varadi, Anyango, Deshpande, Nair, Natassia, Yordanova, Yuan, Stroe, Wood, Laydon, Žídek, Green, Tunyasuvunakool, Petersen, Jumper, Clancy, Green, Vora, Lutfi, Figurnov, Cowie, Hobbs, Kohli, Kleywegt, Birney, Hassabis and Velankar28, Reference Liu, Song, Yan and Liu34). Nevertheless, although these findings collectively support an important role for STOML2 in mitochondrial homeostasis, many of the underlying molecular mechanisms remain incompletely characterised and have largely been investigated in cell-based experimental systems.
Beyond its role in mitochondrial membrane organisation, STOML2 has been implicated in several additional cellular processes. Its reported colocalisation with the COP9 signalosome, a multifunctional protein complex involved in ubiquitin-mediated protein degradation and signal transduction, suggests a potential role in proteostasis and cellular adaptation to stress (Ref. Reference Molina, Grimaldi, Robert-Hebmann, Espert, Varbanov, Devaux, Granier and Biard-Piechaczyk38). Similarly, STOML2 has been shown to colocalise with the T-cell receptor (TCR) complex at the immunological synapse, indicating that it may contribute to T-cell activation and immune signalling (Refs Reference Schmitt, Prokisch, Schlunck, Camp, Ahting, Waizenegger, Scharfe, Meitinger, Imhof, Neupert, Oefner and Rapaport39, Reference Da Cruz, Xenarios, Langridge, Vilbois, Parone and Martinou40). Collectively, these observations indicate that STOML2 may function as an important coordinator of mitochondrial metabolism and immune regulation. However, the precise physiological significance of these interactions and their contribution to human disease remain to be fully established. Accumulating evidence further suggests that dysregulated STOML2 expression may contribute to disorders associated with mitochondrial dysfunction and immune dysregulation, although additional clinical validation is required before these associations can be translated into diagnostic or therapeutic applications (Refs Reference Da Cruz, Xenarios, Langridge, Vilbois, Parone and Martinou40–Reference Kirchhof, Chau, Lemke, Vardhana, Darlington, Márquez, Taylor, Rizkalla, Blanca, Dustin and Madrenas43).
STOML2 expression has also been reported to increase in response to multiple cellular stressors, including oxidative stress (Ref. Reference Aboelella, Brandle, Kim, Ding and Zhou44), metabolic stress (Ref. Reference Repasky, Eng and Hylander45) and hypoxia (Ref. Reference Chen, Han, du, Shi and Zhou46). These adaptive responses are thought to facilitate mitochondrial remodelling and metabolic reprogramming through interactions with other members of the SPFH protein family, particularly PHBs (Ref. Reference Morrow and Parton22). Recent studies have further demonstrated an interaction between STOML2 and mitofusin-2 (MFN2), a dynamin-like GTPase that mediates mitochondrial outer membrane fusion (Ref. Reference Liu, Song, Yan and Liu34). This interaction occurs through the intermembrane-space loop of MFN2 and promotes the formation of hetero-oligomeric complexes within the IMS, thereby establishing a structural and functional connection between the OMM and IMMs (Ref. Reference Hájek, Chomyn and Attardi47). Although this interaction provides a plausible mechanism linking STOML2 to mitochondrial fusion, the extent to which it directly regulates mitochondrial dynamics across different cell types remains incompletely understood. Furthermore, emerging evidence suggests that STOML2 may protect mitochondria against stress-induced hyperfusion; however, these observations remain relatively limited and require validation in additional experimental models (Refs Reference Mootha, Bunkenborg, Olsen, Hjerrild, Wisniewski, Stahl, Bolouri, Ray, Sihag, Kamal, Patterson, Lander and Mann48, Reference Gogvadze, Orrenius and Zhivotovsky49, Reference Tondera, Grandemange, Jourdain, Karbowski, Mattenberger, Herzig, da Cruz, Clerc, Raschke, Merkwirth, Ehses, Krause, Chan, Alexander, Bauer, Youle, Langer and Martinou50).
Within the tumour microenvironment, cancer cells are exposed to persistent metabolic, oxidative and hypoxic stress, all of which profoundly influence mitochondrial function (Ref. Reference De Rasmo, Cormio, Cormio and Signorile15). The increased expression of STOML2 observed under these conditions suggests that it may contribute to mitochondrial adaptation, thereby promoting cellular survival during therapeutic stress. Nevertheless, current evidence is largely derived from experimental studies, and whether STOML2 directly drives these adaptive responses or functions as part of a broader mitochondrial stress–response network remains to be fully determined. Given its strategic localisation within the mitochondrial membrane and its interactions with multiple regulators of mitochondrial homeostasis, STOML2 is increasingly recognised as a potential mediator of mitochondrial dynamics and an attractive candidate for further investigation in cancer biology.
STOML2: A potential regulator of mitochondrial dynamics in chemoresistance
Mitochondrial dynamics, encompassing mitochondrial fission, fusion, mitophagy and mitochondrial biogenesis, are fundamental processes that collectively maintain mitochondrial quality, bioenergetic homeostasis and cellular viability (Ref. Reference Wang, Liu, Cao, Zhang, Huang and Yi11). Disruption of these highly coordinated processes is increasingly recognised as a hallmark of cancer progression and therapeutic resistance, enabling tumour cells to adapt to metabolic stress and evade apoptosis. Alterations in mitochondrial dynamics have been associated with metabolic reprogramming, enhanced proliferative capacity, increased metastatic potential and resistance to anticancer therapies (Refs Reference Dodington, Desai and Woo51, Reference Brooks and Putoczki52) (Figure 2). Given that STOML2 is localised predominantly within the IMM and is frequently overexpressed in several malignancies, accumulating evidence suggests that it may contribute to the dysregulation of mitochondrial dynamics. Nevertheless, the precise molecular mechanisms linking STOML2 to these processes remain incompletely understood and appear to vary across different tumour types. Therefore, understanding the relationship between STOML2 and mitochondrial remodelling may provide new opportunities for improving therapeutic responses while also identifying important gaps that require further mechanistic investigation.
Alterations in mitochondrial dynamics in cancer cells.
Figure 2. Long description
The diagram is divided into four quadrants with a central circular inset.
* Top-Left Panel (F I S S I O N with an upward red arrow): Shows damaged mitochondria being split by a green ring labeled D R P 1 with an upward red arrow. This process leads to an increase in the number of damaged mitochondria.
* Top-Right Panel (F U S I O N with a downward red arrow): Shows healthy and damaged mitochondria attempting to merge. The junction is labeled M F N 1 and M F N 2 with a downward red arrow, indicating inhibited fusion into a healthy mitochondrion.
* Bottom-Right Panel (B I O G E N E S I S with an upward red arrow): Within a cell nucleus, P G C 1 alpha is shown inhibiting N R F 1. Below this, m t D N A Biogenesis is occurring in a new mitochondrion, mediated by T F A M.
* Bottom-Left Panel (M I T O P H A G Y with a downward red arrow): A damaged mitochondrion is shown with surface proteins P A R L, P I N K, N I X, B N I P 3, and F U N D C. It is being targeted by an L C 3 autophagosome membrane. An arrow points to a phagolysosome, but the text indicates a decrease in the clearance of damaged mitochondria.
* Central Inset: A circular view of mitochondrial metabolism. It shows Glucose converting to Pyruvate and then to Lactate or Acetyl-CoA. Acetyl-CoA enters the T C A cycle (including Citrate, alpha K G, Succinyl-CoA, and Oxaloacetate). This process is shown generating A T P and multiple red starbursts labeled R O S (Reactive Oxygen Species).
Mitochondrial dynamics and cancer
Mitochondrial fusion and fission are highly dynamic and tightly regulated processes that maintain mitochondrial morphology, distribution, function and quality control (Ref. Reference Brown and Attardi53). Rather than representing opposing events, fusion and fission function cooperatively to preserve mitochondrial homeostasis and enable rapid adaptation to changing metabolic and environmental conditions. Dysregulation of this balance has been implicated in numerous pathological conditions, including cancer.
Mitochondrial fusion involves the merging of adjacent mitochondria to generate an interconnected mitochondrial network, facilitating the exchange of mitochondrial DNA (mtDNA), proteins, lipids, and metabolic intermediates (Refs Reference Brown and Attardi53, Reference Zhao, Zhang, Yu, Xie, Huang, Wolff, Abel and Tu54). This process is generally considered protective because it allows damaged mitochondrial components to be complemented by functional counterparts, thereby preserving mitochondrial bioenergetics and reducing cellular stress (Ref. Reference Zhao, Zhang, Yu, Xie, Huang, Wolff, Abel and Tu54). Fusion occurs in two coordinated steps: OMM fusion is mediated by mitofusin-1 (MFN1) and mitofusin-2 (MFN2) (Refs Reference Allegra, Innao, Allegra and Musolino55, Reference Habbane, Montoya, Rhouda, Sbaoui, Radallah and Emperador56), whereas IMM fusion is regulated by optic atrophy protein 1 (OPA1) (Refs Reference Porporato, Filigheddu, Pedro, Kroemer and Galluzzi57, Reference von der Malsburg, Sapp, Zuccaro, von Appen, Moss, Kalia, Bennett, Abriata, Dal Peraro, van der Laan, Frost and Aydin58).
Conversely, mitochondrial fission promotes mitochondrial division and is essential for mitochondrial distribution, quality control, organelle turnover and cellular adaptation during proliferation (Refs Reference Filadi, Greotti and Pizzo59, Reference Gao and Hu60, Reference Al Ojaimi, Salah and El-Hattab61). The GTPase dynamin-related protein 1 (DRP1) serves as the principal mediator of mitochondrial fission by translocating from the cytosol to the OMM, where it assembles into oligomeric ring-like structures that constrict and divide mitochondria (Refs Reference Youle and van der Bliek62, Reference Fonseca, Sánchez-Guerrero, Milosevic and Raimundo63). Although fission is indispensable for maintaining mitochondrial quality under physiological conditions, excessive or persistent mitochondrial fragmentation has frequently been associated with tumour progression and resistance to therapy. Fission also facilitates equal mitochondrial distribution during cell division and promotes the selective elimination of damaged mitochondria through mitophagy, thereby preserving mitochondrial integrity (Ref. Reference Berman, Pineda and Hardwick64).
Growing evidence indicates that the balance between mitochondrial fusion and fission is frequently altered in cancer; however, these alterations are highly context dependent and vary considerably among tumour types. Reduced expression of MFN2 has been associated with increased cellular proliferation and resistance to apoptosis in cervical (Ref. Reference Ma, Wang and Jia65) and thyroid cancers (Ref. Reference You, Jeon, Kim, Lee, Cheng, Jang, Kim, Kim, Shong and Kim66). In contrast, elevated DRP1 expression and activity have been reported in lung, breast and colorectal cancers, where enhanced mitochondrial fragmentation supports metabolic reprogramming, facilitates adaptation to hypoxic environments and promotes tumour progression (Ref. Reference Adhikary, Mukherjee, Banerjee and Nagotu67). Nevertheless, it is important to recognise that the functional consequences of altered mitochondrial morphology may differ depending on tumour genetics, metabolic state and microenvironmental conditions, indicating that mitochondrial dynamics cannot be universally classified as either tumour-promoting or tumour-suppressive.
Resistance to apoptosis represents one of the principal mechanisms through which tumour cells survive chemotherapy (Ref. Reference Jensen, Engert, Weissinger, Knauf, Kimby, Poynton, Oliff, Rummel and Österborg68). Numerous studies have suggested that excessive mitochondrial fragmentation reduces the release of cytochrome c and other pro-apoptotic mediators, thereby attenuating activation of the intrinsic apoptotic pathway (Ref. Reference Rodriguez-Antona and Ingelman-Sundberg69). Consequently, elevated DRP1 activity has frequently been associated with resistance to apoptosis in multiple tumour models (Ref. Reference Xiong, Hasani, Young, Rivas, Skaggs, Martinez, Wang, Weiss, Gentry, Sun and Gao70). In addition, anti-apoptotic proteins such as BCL-2 and MCL-1 have been reported to interact with regulators of mitochondrial dynamics, promoting mitochondrial fragmentation and enhancing tumour cell survival (Ref. Reference Tantawy, Timofeeva, Sarkar and Gandhi71). Conversely, increased activity of MFN1, MFN2, and OPA1 promotes mitochondrial elongation and has been associated with enhanced cytochrome c release following apoptotic stimulation, thereby facilitating activation of the caspase cascade (Ref. Reference Wu, Xiao, Li, Huang, You and Li72). Although these observations support the therapeutic potential of manipulating mitochondrial dynamics, the effects of promoting fusion or inhibiting fission remain tumour specific and should therefore be interpreted cautiously. Nevertheless, strategies that restore mitochondrial homeostasis by enhancing fusion or suppressing excessive fission have shown promise in increasing the sensitivity of cancer cells to apoptosis-inducing therapies (Ref. Reference Jeena, Kim, Jin and Ryu73).
Mitophagy represents another essential component of mitochondrial quality control and is frequently dysregulated in cancer, although its biological significance remains highly context dependent (as discussed in section ‘Introduction’). In many tumours, increased mitophagy facilitates the selective removal of damaged mitochondria, thereby limiting oxidative stress, maintaining metabolic flexibility and promoting resistance to chemotherapy and radiotherapy. Conversely, reduced mitophagy in certain malignancies results in the accumulation of dysfunctional mitochondria, increased reactive oxygen species (ROS) production, genomic instability and altered cellular signalling that may either promote or suppress tumour progression depending on the biological context (Ref. Reference Xu, Xue, Bankhead and Neamati74). This dual role highlights one of the major challenges in therapeutically targeting mitophagy, as both excessive and insufficient mitophagic activity may influence tumour behaviour in different ways.
Consequently, modulation of mitochondrial dynamics has emerged as an attractive therapeutic strategy for overcoming chemoresistance (Refs Reference Zhao, Li, Zhou, Peng, Zheng, Chen and Ding75, Reference Denisenko, Gogvadze and Zhivotovsky76). Pharmacological inhibition of mitochondrial fission, particularly through targeting DRP1, has been reported to reduce glycolytic metabolism, increase dependence on OXPHOS and enhance susceptibility to apoptosis in several preclinical models (Refs Reference Zhao, Li, Zhou, Peng, Zheng, Chen and Ding75, Reference Deepak, Roy, das, Mukherjee and Mandal77). However, these responses are not universal and vary according to tumour type and metabolic phenotype, emphasising the importance of tumour-specific therapeutic approaches. DRP1 inhibitors such as Mdivi-1 have demonstrated the ability to reduce tumour cell proliferation and improve chemotherapy sensitivity in experimental studies (Ref. Reference Silva-Pavez, Mendoza, Morgado-Cáceres, Ahumada-Castro, Bustos, Kangme-Encalada, de Arbina, Puebla-Huerta, Muñoz, Cereceda, Varas-Godoy, Hidalgo and Cardenas78). Similarly, therapeutic approaches that promote mitochondrial fusion through activation of MFN1, MFN2 or OPA1 have been associated with restoration of mitochondrial function and increased apoptotic sensitivity, particularly when combined with conventional anticancer therapies.
Targeting mitophagy represents an additional therapeutic opportunity for overcoming chemoresistance (Ref. Reference Li and Huang79). Rather than uniformly activating or inhibiting mitophagy, future therapeutic strategies will likely require precise modulation according to tumour-specific mitochondrial phenotypes. In cancers characterised by impaired mitophagy, restoring mitochondrial turnover may improve mitochondrial quality control and cellular homeostasis. Conversely, in tumours exhibiting excessive mitophagic activity, inhibition of mitophagy may promote the accumulation of dysfunctional mitochondria, elevate ROS production and ultimately enhance cancer cell death (Ref. Reference Dong and Zhang80). Collectively, these observations suggest that the therapeutic modulation of mitochondrial dynamics holds considerable promise; however, additional mechanistic and clinical studies are required to define the patient populations most likely to benefit from these approaches.
Although the fundamental mechanisms governing mitochondrial fusion, fission and mitophagy have been extensively characterised, the contribution of STOML2 to coordinating these interconnected processes remains an emerging area of investigation. Owing to its strategic localisation within the IMM and its interactions with key mitochondrial proteins, STOML2 has been proposed to function as a molecular scaffold that supports mitochondrial organisation and quality control. However, the extent to which STOML2 directly regulates individual components of the mitochondrial dynamics machinery, rather than acting indirectly through alterations in mitochondrial homeostasis, remains incompletely understood. The following sections critically examine the current evidence linking STOML2 to mitochondrial fusion, fission, mitophagy and mitochondrial biogenesis, while distinguishing experimentally validated findings from proposed mechanistic models.
Intricate relationship between STOML2, mitochondrial dynamics and chemoresistance
Chemoresistance develops through a complex network of adaptive cellular responses that collectively enable tumour cells to survive the cytotoxic effects of chemotherapy (Ref. Reference Brasseur, Gévry and Asselin81). Among these, the DNA damage response (DDR) represents one of the principal mechanisms by which cancer cells repair chemotherapy-induced DNA lesions and evade apoptosis (Refs Reference Mansoori, Mohammadi, Davudian, Shirjang and Baradaran82, Reference Lu and Shervington83, Reference Hanahan and Weinberg84). Chemotherapeutic agents also induce oxidative stress by generating excessive ROS (Ref. Reference Barrera, Cucci, Grattarola, Dianzani, Muzio and Pizzimenti85). To counteract this stress, tumour cells activate antioxidant defence mechanisms, including glutathione synthesis and nuclear factor erythroid 2-related factor 2 (Nrf2) signalling, thereby restoring redox homeostasis and promoting survival (Refs Reference Yeldag, Rice and del Río Hernández86–Reference Cecconi and Levine89). In parallel, alterations in apoptotic signalling, characterised by increased expression of anti-apoptotic proteins such as BCL-2 and reduced expression of pro-apoptotic mediators including BAX, further enhance resistance to programmed cell death (Refs Reference Maji, Panda, Samal, Shriwas, Rath, Pellecchia, Emdad, das, Fisher and Dash90, Reference Qian, Wei, Yang, Huang, Yang and Wang91). Cancer cells also undergo adaptive changes in cell-cycle regulation by arresting in the G0/G1 or G2/M phases, thereby reducing their susceptibility to chemotherapeutic agents that preferentially target rapidly proliferating cells (Refs Reference Zhao92, Reference Senthebane, Rowe, Thomford, Shipanga, Munro, Mazeedi, Almazyadi, Kallmeyer, Dandara, Pepper, Parker and Dzobo93). Furthermore, activation of pro-survival signalling pathways, including PI3K/AKT, MAPK/ERK, and NF-κB, provides additional protection against chemotherapy-induced apoptosis (Ref. Reference Godwin, Baird, Heavey, Barr, OByrne and Gately94).
Additional resistance mechanisms include increased drug efflux mediated by ATP-binding cassette (ABC) transporters such as P-glycoprotein, which reduce intracellular drug accumulation and consequently diminish therapeutic efficacy (Refs Reference Godwin, Baird, Heavey, Barr, OByrne and Gately94, Reference Sharom95). The tumour microenvironment further enhances chemoresistance by providing metabolic and survival signals through stromal cells, immune cells and extracellular matrix components (Ref. Reference Yu, Lee, Herrmann, Buettner and Jove96). Stress granule formation has also emerged as an adaptive response that promotes cancer cell survival by temporarily suppressing apoptosis during chemotherapy (Ref. Reference Sharom95). Collectively, these mechanisms establish a highly coordinated stress-adaptation network that enables tumour cells to withstand therapeutic pressure (Refs Reference Yu, Lee, Herrmann, Buettner and Jove96, Reference Kong, Tsuyoshi, Orisaka, Shieh, Yoshida and Tsang97). Importantly, accumulating evidence suggests that STOML2 may interact with several of these adaptive pathways; however, the majority of current evidence has been derived from experimental cell models, and direct mechanistic validation across different cancer types remains limited.
In addition to these well-established mechanisms of chemoresistance, increasing attention has focused on the contribution of mitochondrial dynamics to therapeutic adaptation. Alterations in mitochondrial fusion, fission, mitophagy and mitochondrial quality control allow tumour cells to rapidly remodel their metabolism in response to chemotherapy-induced stress. Owing to its localisation within the IMM, STOML2 has emerged as a potential regulator of these adaptive mitochondrial responses. Nevertheless, whether STOML2 functions as a primary driver of chemoresistance or acts as one component of a broader mitochondrial stress–response network remains an important unresolved question.
Current evidence suggests that STOML2 may influence multiple aspects of mitochondrial dynamics, including mitochondrial fusion, fission and mitophagy (Refs Reference Qin, Wang, Zhao, Li, Li, Yang, Zhao and Wang14, Reference Arakaki, Nishihama, Owaki, Kuramoto, Suenaga, Miyoshi, Emoto, Shibata, Shono and Higuti98). Experimental studies have reported that STOML2 contributes to the maintenance of mitochondrial integrity by promoting mitochondrial fusion and facilitating the removal of dysfunctional mitochondria, thereby supporting mitochondrial function during cellular stress (Refs Reference Qin, Wang, Zhao, Li, Li, Yang, Zhao and Wang14, Reference Arakaki, Nishihama, Owaki, Kuramoto, Suenaga, Miyoshi, Emoto, Shibata, Shono and Higuti98). Furthermore, STOML2 has been shown to interact with mitofusin-2 (MFN2), forming hetero-oligomeric complexes that may stabilise mitochondrial fusion machinery (Refs Reference Arakaki, Nishihama, Owaki, Kuramoto, Suenaga, Miyoshi, Emoto, Shibata, Shono and Higuti98, Reference Wai and Langer99). Because mitochondrial fusion depends upon preservation of the mitochondrial membrane potential, disruption of STOML2 expression has been proposed to impair mitochondrial membrane integrity, resulting in an imbalance between fusion and fission dynamics (Ref. Reference Ma, Chen, Xiong, Li, Xu, Wang, Wei, Mou, Wu, Cheng, Zou, Zhu, Zhou, Liu and Geng16). Reduced STOML2 expression has been associated with mitochondrial depolarisation and increased recruitment of DRP1 to the mitochondrial surface, thereby favouring mitochondrial fragmentation (Refs Reference Lee, Jeong, Karbowski, Smith and Youle100–Reference Tilokani, Nagashima, Paupe and Prudent103). Although these findings strongly suggest that STOML2 contributes to the regulation of mitochondrial morphology, additional mechanistic studies are required to determine whether these effects are direct or secondary to broader alterations in mitochondrial homeostasis.
STOML2 has also been implicated in regulating mitophagy through the PARL–PINK1 signalling axis. Under physiological conditions, PARL-mediated cleavage promotes degradation of PINK1 within healthy mitochondria. Experimental evidence suggests that reduced STOML2 expression destabilises PARL, thereby impairing PINK1 processing and permitting its accumulation on the OMM. Accumulated PINK1 subsequently recruits Parkin, leading to activation of the PINK1/Parkin-dependent mitophagy pathway (Refs Reference Jin and Youle104, Reference Panigrahi, Praharaj, Bhol, Mahapatra, Patra, Behera, Mishra and Bhutia105). Although this pathway has been demonstrated in experimental systems, its contribution to chemoresistance may differ among tumour types and remains an active area of investigation. Consequently, caution should be exercised when extrapolating these mechanistic findings across different cancers.
Collectively, current evidence supports a close association between STOML2, mitochondrial dynamics and therapeutic adaptation. However, many of the proposed mechanisms have been established primarily through gene-silencing experiments and in vitro cancer models, whereas validation in animal models and clinical specimens remains comparatively limited. Future studies integrating functional genomics, advanced imaging and patient-derived tumour models will be essential to determine whether STOML2 functions as a clinically actionable regulator of chemoresistance or represents a biomarker reflecting broader alterations in mitochondrial homeostasis. The proposed mechanisms through which STOML2 overexpression may influence mitochondrial dynamics, oxidative stress responses, survival signalling and chemoresistance are summarised in Figure 3.
Anticancer drug exposure induces cellular stress and is associated with increased STOML2 expression. STOML2 is involved in mitochondrial dynamics and the STOML2–PARL axis, influencing PINK1 processing, Parkin recruitment and mitophagy. Altered mitochondrial dynamics and quality control may contribute to ROS accumulation, antioxidant responses, survival signalling and reduced apoptosis, potentially promoting chemoresistance. Solid arrows indicate experimentally supported relationships, whereas dashed arrows indicate proposed or inferred mechanisms requiring further validation. Downstream effects may vary among tumour types and experimental systems.
Figure 3. Long description
A flowchart within a cell diagram.
* Top Left: Anticancer Drug molecules lead to Activation of stress response, which causes Overexpression of S T O M L 2.
* Middle Left: A mitochondrion shows S T O M L 2 accumulation. Two solid arrows lead to signaling boxes.
* Top Signaling Box: Interaction with M F N 2 supports Mitochondrial Fusion Machinery. A dashed arrow leads to a seesaw diagram showing an imbalance: Fission with D R P 1 is increased (red up arrow), while Fusion with O P A 1 is decreased (red down arrow).
* Bottom Signaling Box: S T O M L 2 dash P A R L axis shows decreased P A R L Stability, increased P I N K Accumulation, Parkin recruitment, and increased Mitophagy (red up arrow).
* Center: A dashed arrow from the fission/fusion imbalance leads to a cluster of A T P and R O S (Reactive Oxygen Species) symbols.
* Right Side: Dashed lines from the R O S cluster lead to three outcome boxes, all with red up arrows: Antioxidant pathway expression (glutathione), Cell proliferation Pathways (e.g. P I 3, N r f etc.), and Antiapoptotic protein expression (e.g. B c l dash 2).
* Bottom Center: A dashed arrow from the S T O M L 2 dash P A R L axis leads to a Mitophagy event.
* Bottom Right: All pathways converge at a final box labeled Enhanced Survival and Chemoresistance.
* Legend: Solid arrows indicate Experimentally Validated mechanisms; dashed arrows indicate Proposed mechanisms requiring further validation.
Beyond its proposed role in regulating mitochondrial dynamics, accumulating evidence suggests that STOML2 may influence several oncogenic signalling pathways that coordinate tumour cell survival, proliferation, metabolic adaptation and therapeutic resistance. The following sections critically examine the current evidence linking STOML2 with these signalling networks while distinguishing experimentally validated interactions from emerging mechanistic hypotheses.
STOML2 in cellular signalling pathways within the tumour microenvironment
Increasing evidence indicates that STOML2 is aberrantly overexpressed in multiple malignancies, including glioblastoma (Ref. Reference Song, Liu, Wu, Lin, Dai, Yu, Wang, Wu, Li and Li106), colorectal cancer (Ref. Reference Arakaki, Nishihama, Owaki, Kuramoto, Suenaga, Miyoshi, Emoto, Shibata, Shono and Higuti98) and ovarian cancer (Refs Reference Cheng, Yu, Kong, Wang, Shen, Dong and Sun107, Reference Milisav, Poljšak and Ribarič108), where its expression has frequently been associated with aggressive tumour behaviour, poor prognosis and therapeutic resistance. Within the tumour microenvironment, cancer cells are continuously exposed to hypoxia, nutrient deprivation, oxidative stress and inflammatory stimuli, all of which require extensive metabolic adaptation to sustain survival. Several experimental studies suggest that STOML2 contributes to these adaptive responses by preserving mitochondrial function, maintaining bioenergetic homeostasis and limiting the accumulation of dysfunctional mitochondria (Ref. Reference Qin, Wang, Zhao, Li, Li, Yang, Zhao and Wang14). In addition to its role in mitochondrial quality control, STOML2 has been implicated in multiple oncogenic signalling pathways that regulate tumour cell proliferation, survival, invasion and resistance to chemotherapy (Figure 4). However, it is important to recognise that many of these signalling interactions have been demonstrated in individual tumour models and may not represent universally conserved mechanisms across different cancer types. Consequently, the available evidence should be interpreted within the context of the experimental systems in which these observations were made.
STOML2-associated signalling pathways involved in tumour progression and therapeutic resistance. The schematic summarises signalling pathways associated with STOML2 overexpression, including NF-κB, MAPK, PINK1/Parkin, IL-6–JAK/STAT and MEK/ERK pathways, and their reported effects on tumour survival, proliferation, invasion, mitophagy, angiogenesis and chemoresistance. Solid lines indicate relationships supported by experimental evidence, whereas dashed lines indicate proposed or inferred associations requiring further validation.
Figure 4. Long description
The flowchart is divided into three main vertical sections.
1. Cellular Origin (Left): A cross-section of a cell shows a mitochondrion with upward red arrows indicating Overexpression of S T O M L 2. This is bounded by a dashed blue line labeled Cell Membrane.
2. Pathway (Center): Five circular nodes represent signaling pathways, each connected to a text box describing its effect.
- N F kappa B Pathway: Metastasis and invasiveness of cancer.
- M A P K Pathway: Cancer survival and proliferation.
- P I N K 1 / Parkin Pathway: Reduced mitophagy and increased chemoresistance.
- I L 6 / J A K S T A T Pathway: Survival, angiogenesis, immune modulation and differentiation, chronic inflammation and resistance.
- M E K / E R K Pathway: Cancer development, progression and survival.
3. Function (Right): A vertical column of biological illustrations corresponds to the outcomes. From top to bottom: Cell survival, Cell Proliferation, Angiogenesis, Metastasis, Reduced Mitophagy (marked with a red X), and Chemoresistance.
Evidence Status (Bottom Legend): Solid lines with black circles indicate relationships supported by experimental evidence (top three pathways). Dashed lines with white circles indicate proposed associations requiring further validation (bottom two pathways).
NF-κB/MMP-9 signalling pathway
The nuclear factor-κB (NF-κB) signalling pathway represents one of the principal regulators of inflammation, cell survival, immune responses and tumour progression. Dysregulated NF-κB activation has been implicated in multiple cancers through its ability to promote proliferation, inhibit apoptosis and facilitate metastatic dissemination. Experimental studies in glioma have demonstrated that reducing STOML2 expression markedly decreases the invasive capacity of tumour cells (Ref. Reference Ma, Chen, Xiong, Li, Xu, Wang, Wei, Mou, Wu, Cheng, Zou, Zhu, Zhou, Liu and Geng16). This reduction has been accompanied by suppression of NF-κB signalling, resulting in decreased expression of several downstream genes involved in inflammation, cell survival and tumour progression (Ref. Reference Song, Liu, Wu, Lin, Dai, Yu, Wang, Wu, Li and Li106).
Among these downstream targets, matrix metalloproteinase-9 (MMP-9) plays a particularly important role in extracellular matrix degradation, tumour invasion and metastatic dissemination (Ref. Reference Jiang, Bai, Xie, Guo, Li and Ma109). Silencing STOML2 has been reported to reduce MMP-9 expression, suggesting that STOML2 may indirectly promote glioma invasiveness through modulation of the NF-κB/MMP-9 signalling axis (Ref. Reference Song, Liu, Wu, Lin, Dai, Yu, Wang, Wu, Li and Li106). Although these observations support an association between STOML2 and NF-κB-mediated invasion, current evidence is largely derived from glioma cell models. Consequently, whether this regulatory mechanism operates similarly across other malignancies remains uncertain and requires further validation in vivo and in clinical cohorts.
Collectively, available studies suggest that STOML2 may facilitate tumour invasion by enhancing NF-κB-dependent transcriptional programmes; however, direct molecular interactions between STOML2 and components of the NF-κB signalling cascade have not yet been fully elucidated. Future mechanistic studies will therefore be required to determine whether STOML2 functions as a direct upstream regulator of NF-κB signalling or whether its effects arise indirectly through alterations in mitochondrial homeostasis and cellular stress responses.
MAPK signalling pathway
The mitogen-activated protein kinase (MAPK) signalling pathway is a central regulator of cellular proliferation, differentiation, survival and stress adaptation and its dysregulation is frequently observed in colorectal cancer (CRC) (Ref. Reference Ma, Chen, Xiong, Li, Xu, Wang, Wei, Mou, Wu, Cheng, Zou, Zhu, Zhou, Liu and Geng16). Activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), major downstream effectors of the MAPK pathway, promotes tumour cell proliferation, survival and metabolic adaptation within the tumour microenvironment (Ref. Reference Fang and Richardson110).
Several studies have suggested that STOML2 may influence MAPK signalling through its interaction with prohibitin-2 (PHB2), a multifunctional mitochondrial scaffold protein involved in mitochondrial organisation and intracellular signalling (Ref. 111). Overexpression of STOML2 has been associated with altered PHB2 activity in both human colorectal cancer cell lines (HCT116, HT29, SW480 and SW620) and murine models (MC38 and CT26) (Ref. Reference Guo, Pan, Liu, Shen, Xu and Hu112). Conversely, knockdown of STOML2 has been reported to reduce ERK1/2 phosphorylation, resulting in diminished activation of the MAPK signalling pathway (Ref. Reference Kyriakis and Avruch113).
These findings collectively suggest that STOML2 may contribute to MAPK pathway activation by modulating PHB2-dependent signalling. Nevertheless, the majority of available evidence has been generated using experimental cell models, and the precise molecular mechanism linking STOML2 to MAPK activation remains incompletely understood. Furthermore, it remains unclear whether STOML2 directly regulates PHB2 function or whether these effects occur secondary to broader alterations in mitochondrial organisation and bioenergetics.
From a translational perspective, disruption of the STOML2–PHB2 interaction represents a potentially attractive therapeutic strategy because it may simultaneously impair mitochondrial homeostasis and oncogenic MAPK signalling (Refs Reference De Rasmo, Cormio, Cormio and Signorile15, Reference Eblen114). However, given the essential physiological functions of PHB2 and MAPK signalling in normal tissues, additional studies are required to evaluate the specificity, safety and clinical feasibility of targeting this regulatory axis.
PINK1–Parkin signalling pathway
The PINK1/Parkin pathway represents one of the best-characterised mechanisms regulating mitochondrial quality control through selective mitophagy. Under physiological conditions, PINK1 is continuously imported into healthy mitochondria, where it undergoes PARL-mediated proteolytic cleavage, leading to its degradation and preventing unnecessary activation of mitophagy (Ref. Reference Jin and Youle104). Maintenance of this regulatory mechanism is essential for preserving mitochondrial homeostasis under basal conditions.
Emerging evidence suggests that STOML2 contributes to the stability and function of the PARL protease complex through direct or indirect interactions within the IMM (Ref. Reference De Rasmo, Cormio, Cormio and Signorile15). Experimental studies have demonstrated that depletion of STOML2 destabilises PARL, thereby impairing PINK1 processing and allowing full-length PINK1 to accumulate on the OMM (Ref. Reference Jin and Youle104). Accumulated PINK1 subsequently recruits the E3 ubiquitin ligase Parkin, initiating ubiquitination of OMM proteins and activation of the PINK1/Parkin-dependent mitophagy pathway (Ref. Reference Panigrahi, Praharaj, Bhol, Mahapatra, Patra, Behera, Mishra and Bhutia105).
These observations indicate that STOML2 may influence mitochondrial quality control by regulating PARL-dependent PINK1 turnover. Nevertheless, most mechanistic evidence supporting this pathway has been generated using gene-silencing approaches and experimental cell models, whereas validation in diverse tumour types and clinical specimens remains comparatively limited. Furthermore, the extent to which STOML2-mediated regulation of mitophagy directly contributes to chemoresistance, rather than reflecting broader alterations in mitochondrial homeostasis, remains incompletely understood.
Altered regulation of the PINK1/Parkin pathway may have important consequences for therapeutic response. Reduced mitophagy may impair the efficient removal of dysfunctional mitochondria, increasing susceptibility to oxidative stress and chemotherapy-induced damage. Conversely, excessive mitophagy may facilitate mitochondrial quality control and promote tumour cell survival under therapeutic stress. These observations indicate that the functional consequences of STOML2-mediated regulation cannot be considered uniformly oncogenic but instead depend on the biology of how mitochondrial quality control is altered (Ref. Reference De Rasmo, Cormio, Cormio and Signorile15).
IL-6–JAK/STAT signalling pathway
The interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway is a major regulator of cell proliferation, survival, immune modulation, inflammation and therapeutic resistance (Ref. Reference Zhang, Lu, Hong, Liu, Wang, Zhou, Chen and Bai115). Persistent activation of STAT3 and STAT5 promotes transcription of cell-cycle regulators including c-Myc and Cyclin D, thereby sustaining uncontrolled tumour proliferation (Refs Reference Liu, Wang, Wang, Yin, Liu, Lei and Xiang116, Reference Wang, Cao, Yu and Liu117). In addition, STAT signalling enhances the expression of anti-apoptotic proteins such as BCL-2 and BCL-xL, contributing to resistance against chemotherapy-induced apoptosis and promoting tumour cell survival (Ref. Reference Bharti, Dey and Mandal118). The IL-6–JAK/STAT pathway has also been implicated in the maintenance of cancer stem cells (CSCs), metabolic reprogramming and tumour recurrence, enabling malignant cells to survive within hostile tumour microenvironments (Ref. Reference Hu, li, Fu, Zhao and Wang119).
Several studies have suggested that STOML2 functions as an oncogenic regulator capable of influencing multiple downstream signalling pathways (Ref. Reference Wang, Cao, Yu and Liu117). Recent experimental evidence indicates that increased STOML2 expression is associated with enhanced IL-6 production and subsequent activation of the JAK/STAT3 signalling cascade (Ref. Reference Blanke, Sacco, Millikan, Olshan, Luo and Trepanier120). Activation of this pathway has been linked to increased tumour cell proliferation, angiogenesis, immune modulation and metastatic progression in several malignancies (Refs Reference Huang, Lang and Li121, Reference Johnson, OKeefe and Grandis122, Reference Hu, Bian, Rong, Wang, Song, Huang, Zeng, Mei and Wang123). Persistent activation of IL-6–JAK/STAT signalling during chronic inflammation has likewise been associated with carcinogenesis, tumour progression and reduced sensitivity to conventional anticancer therapies (Ref. Reference Wu, Cao, Lu, Zhang, Sethi and You124). Consistent with these observations, enhanced IL-6–STAT3 signalling has been reported in multiple malignancies, including colorectal, gastrointestinal and cervical cancers (Ref. Reference Kumari, Dwarakanath, das and Bhatt125).
In head and neck squamous cell carcinoma (HNSCC), STOML2 overexpression has been reported to increase STAT3 phosphorylation, thereby enhancing STAT3 transcriptional activity (Ref. Reference Xie, Wei, Ruan, Zhang and Shi126). Consequently, elevated STOML2 expression has been associated with increased expression of multiple oncogenic genes involved in tumour progression, while modulation of the IL-6–STAT3 axis may additionally influence the expression of genes implicated in chemotherapy resistance (Ref. Reference Qu, Jiang, Wang and Chen127). Although these findings support a functional association between STOML2 and IL-6–JAK/STAT signalling, the majority of evidence remains tumour specific and direct molecular interactions between STOML2 and pathway components have not yet been fully established.
IL-6 is generally regarded as a pro-tumorigenic cytokine because sustained activation of IL-6–JAK/STAT3 signalling promotes tumour cell proliferation, survival, angiogenesis, immune evasion and therapeutic resistance. Persistent STAT3 activation increases expression of multiple survival-associated genes, including BCL-2, Cyclin D1 and c-Myc, thereby establishing a positive inflammatory feedback loop that supports continuous tumour growth (Refs Reference Rah, Rather, Bhat, Baba, Mushtaq, Farooq, Yousuf, Dar, Parveen, Hassan, Mohammad, Qassim, Bhat, Ali, Zargar and Afroze128, Reference Zhou, Song, Yuan and Li129).
However, the biological functions of IL-6 are highly context dependent and should not be considered exclusively tumour promoting. During acute immune responses and the early stages of anti-tumour immunity, IL-6 contributes to activation of T lymphocytes and natural killer (NK) cells, thereby enhancing immune surveillance and facilitating recognition and elimination of transformed cells (Ref. Reference Wu, Cao, Lu, Zhang, Sethi and You124). These apparently opposing roles largely reflect differences in the duration of IL-6 signalling, cellular context and tumour stage. Acute, transient IL-6 signalling may support protective immune responses, whereas chronic and sustained activation of the IL-6–JAK/STAT pathway promotes tumour progression and resistance to therapy. Consequently, current evidence suggests that the oncogenic effects associated with STOML2 are more likely related to persistent activation of IL-6/JAK–STAT3 signalling rather than its physiological immunostimulatory functions.
MEK–ERK signalling pathway
The mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signalling pathway is a major regulator of cell proliferation, differentiation, survival and resistance to cellular stress. Persistent activation of this pathway has been implicated in the development of chemoresistance across multiple malignancies by promoting tumour cell survival and suppressing apoptosis.
Experimental studies in cervical cancer have demonstrated that cisplatin treatment increases STOML2 expression in HeLa and SiHa cells, accompanied by enhanced phosphorylation of MEK and ERK, suggesting activation of the MEK/ERK signalling cascade (Ref. Reference Hu, Zhang, Xu, Deng, Zhang, Kang and Liang130). Sustained MEK/ERK activation has been associated with increased expression of anti-apoptotic proteins such as BCL-2 and reduced expression of the pro-apoptotic protein BAX, thereby favouring tumour cell survival following chemotherapy (Refs Reference de Araújo, Lôbo, Trindade, Silva and Pereira131, Reference Khan, Kuttikrishnan, Siveen, Prabhu, Shanmugakonar, al- Naemi, Haris, Dermime and Uddin132).
In addition to regulating survival signalling, STOML2 has been proposed to influence the intrinsic mitochondrial apoptotic pathway through interactions with mitochondrial apoptotic regulators. Experimental evidence suggests that increased STOML2 expression may reduce cytochrome c release from mitochondria, thereby limiting activation of downstream caspases and suppressing apoptosis (Refs Reference Reece, Song, Hancock, Pereira Ribeiro, Kulpa and Gavegnano133, Reference Zhang, Mathews Griner, Ju, Duveau, Guha, Petrus, Wen, Maeda, Shinn, Ferrer, Conlon, Bamford, OShea, Thomas and Waldmann134). However, the precise molecular mechanisms linking STOML2 with mitochondrial apoptosis remain incompletely understood, and most available evidence has been generated using experimental cancer models rather than clinical samples. Consequently, further mechanistic and translational studies are required before this pathway can be considered a validated therapeutic target.
Collectively, current evidence suggests that STOML2 may facilitate activation of MEK/ERK signalling under chemotherapy-induced stress, thereby contributing to tumour cell adaptation and survival. Nevertheless, whether STOML2 directly regulates MEK/ERK signalling or influences this pathway indirectly through mitochondrial remodelling remains an important unresolved question.
Integration of STOML2-associated signalling networks
Although the individual signalling pathways discussed above have each been associated with STOML2 expression, increasing evidence indicates that these pathways function as components of an interconnected regulatory network rather than as isolated signalling modules. Importantly, the strength of evidence supporting each interaction differs considerably, and several proposed pathway connections remain hypothetical or tumour specific.
Among the best-characterised interactions is the relationship between NF-κB and IL-6–JAK/STAT signalling. Activation of NF-κB promotes transcription of IL-6, which subsequently activates the JAK/STAT3 pathway, thereby linking inflammatory signalling with tumour cell proliferation and survival (Ref. Reference Zhang, Mathews Griner, Ju, Duveau, Guha, Petrus, Wen, Maeda, Shinn, Ferrer, Conlon, Bamford, OShea, Thomas and Waldmann134). Persistent NF-κB activation has been associated with sustained IL-6 production, leading to prolonged STAT3 activation and increased expression of anti-apoptotic proteins including BCL-2 and BCL-xL (Ref. Reference Taniguchi and Karin135). This positive feedback mechanism has been proposed to reinforce chronic inflammation, tumour progression, immune evasion and therapeutic resistance. In addition, NF-κB-dependent upregulation of MMP-9 promotes extracellular matrix degradation and facilitates tumour invasion (Ref. Reference Song, Liu, Wu, Lin, Dai, Yu, Wang, Wu, Li and Li106).
The MAPK and MEK/ERK pathways exhibit extensive functional interactions with both NF-κB and JAK/STAT signalling. ERK-mediated phosphorylation of multiple transcription factors enhances mitogenic signalling and promotes tumour cell proliferation (Refs Reference Milisav, Poljšak and Ribarič108, Reference Jiang, Bai, Xie, Guo, Li and Ma109). Experimental studies have further suggested that activated ERK may enhance STAT3 transcriptional activity, while MEK/ERK signalling has also been reported to stimulate NF-κB activation through IKK phosphorylation or increased IL-6 production. Conversely, cytokine-mediated activation of JAK/STAT signalling may activate the Ras–Raf–MEK–ERK cascade, thereby establishing reciprocal communication between inflammatory and mitogenic signalling pathways (Ref. Reference Wang, van Boxel-Dezaire, Cheon, Yang and Stark136). Although these interactions have been reported in several experimental models, their relative importance appears to differ substantially according to tumour type, genetic background and microenvironmental conditions.
Mitochondrial quality control mediated by the PINK1/Parkin pathway also interacts closely with cytoplasmic signalling networks. Dysregulation of STOML2 or PARL may impair mitophagy, resulting in accumulation of dysfunctional mitochondria and increased production of ROS (Ref. Reference Qin, Wang, Zhao, Li, Li, Yang, Zhao and Wang14). Elevated ROS function as secondary signalling messengers capable of activating NF-κB, MAPK and JAK/STAT pathways, thereby linking mitochondrial dysfunction with pro-survival signalling (Ref. Reference Glorieux, Liu, Trachootham and Huang137). Within hypoxic tumour microenvironments, ROS additionally stabilise hypoxia-inducible factor-1α (HIF-1α), promoting IL-6 expression and further amplifying the NF-κB–IL-6–STAT3 signalling axis (Ref. Reference Shi, Liao and Zhang138). Nevertheless, it should be emphasised that many of these pathway interactions have been inferred from independent experimental studies rather than being demonstrated simultaneously within a single biological system. Consequently, the proposed signalling network should be regarded as an integrated working model rather than a universally established molecular mechanism.
Overall, accumulating evidence supports the concept that STOML2 may function as an important mitochondrial signalling hub capable of influencing multiple pathways involved in tumour progression, metabolic adaptation and therapeutic resistance. However, the available evidence remains heterogeneous and is derived predominantly from cell-based studies, with comparatively limited validation in animal models and patient-derived samples. Future investigations employing multi-omics approaches, single-cell analyses, spatial transcriptomics and functional studies in clinically relevant tumour models will be essential to determine the precise contribution of STOML2 to these signalling networks and to evaluate its suitability as a prognostic biomarker or therapeutic target.
Therapeutic targeting of STOML2: Current strategies and experimental evidence
Recent studies across multiple malignancies have considerably expanded our understanding of the biological functions of STOML2 and its contribution to tumour progression and chemoresistance. Aberrant STOML2 expression has been consistently associated with aggressive clinicopathological characteristics, including poor differentiation, lymph-node metastasis, advanced tumour stage and reduced patient survival in several cancers (Refs Reference Guo, Liang, Wang, Zhou, Yin, Zhang, Wang, Wu, Ma, Liu, Sun, Ji, Li, Zhou, Yang, Guo, Cui, Li, Liu, Wang and Liu139, Reference Zhang, Wu, Feng, Lu and Liu140, Reference Li, He, Yan, Li, Cao, Huang and Zhou141). These observations have stimulated growing interest in evaluating STOML2 as both a prognostic biomarker and a potential therapeutic target. Experimental studies have further demonstrated that genetic suppression of STOML2 enhances the sensitivity of tumour cells to conventional anticancer therapies across multiple cancer models (Table 1).
Overview of the strategies used to target STOML2 across different cancer types
Table 1. Long description
The table consists of 11 entries across 7 columns.
1. Cervical cancer: Studied in H E L A and S I H A cells using s i R N A and Cisplatin, affecting the M E K forward slash E R K pathway.
2. Head and neck squamous cell cancer: Studied in S C C 25, S C C 15, C A L 27, T S C C 1, and Tca-8113 cells using s i R N A and Cisplatin, affecting I L 6-Stat3 and N F-K B forward slash M M P-9 pathways.
3. Colorectal cancer: Studied in human C R C cell lines H C T 116, H T 29, S W 480, S W 620 and murine lines M C 38, C T 26 using sh S T O M L 2 with Fluorouracil plus Sorafenib, affecting the M A P K pathway.
4. Hepatocellular cancer: Studied in S M M C-7721 and H C C L M 3 using sh R N A with Lenvatinib plus Hydroxychloroquine, affecting P I N K-Parkin mediated pathways.
5. Hepatocellular cancer: Studied in Huh-7, Hep-G2, H C C L M 3, and S N U-387 using Ruxolitinib, affecting the J A K-S T A T pathway.
6. Ovarian cancer: Studied in A 2780 cells using Cisplatin, affecting the M E K forward slash E R K pathway.
7. Pancreatic cancer: Studied in P A N C 1, B x P C-3, M I A PaCa-2, P A T U 8 9 8 8 T cell lines, and B A L B forward slash c nude mice using si S T O M L 2 and Gemcitabine, affecting P I N K-Parkin mediated pathways.
8. Non-small cell lung cancer: Studied in A 5 4 9 forward slash P T X cells using Resveratrol and m i R-671-5p mimic with Paclitaxel, affecting P I N K-Parkin mediated pathways.
9. Hepatocellular cancer: Studied in Huh 7 and M H C C 9 7 H cells using sh R N A and 5-fluorouracil, affecting c-M Y C forward slash Cyclin D 1 forward slash p 21.
10. Hepatocellular cancer: Studied in Huh 7 cells using s i R N A and C R I S P R forward slash Cas 9 knockout with Sorafenib, affecting P I N K-Parkin mediated pathways.
11. Hepatocellular cancer: Studied in Huh 7, H E P 3 B, and L M 3 cells using sh R N A and Sorafenib, affecting the A K T-S L C 7 A 11 antioxidant pathway.
Elevated STOML2 expression has been reported in gastric adenocarcinoma, cervical cancer, oral squamous cell carcinoma, epithelial ovarian cancer, hepatocellular carcinoma, pancreatic cancer and several other malignancies, where increased expression is generally associated with more aggressive tumour behaviour and poorer clinical outcomes (Refs Reference Li, He, Yan, Li, Cao, Huang and Zhou141, Reference Wang, Qi, Li, Deng, Xu, Hu, Liu and Wang147, Reference Sun, Ding, He, Wang, Ma and Li148). Although these findings strongly support the oncogenic potential of STOML2, most available evidence has been derived from experimental cell models and retrospective patient cohorts. Consequently, prospective clinical validation is still required before STOML2 can be considered a clinically useful therapeutic target or biomarker.
siRNA-mediated knockdown of STOML2
Among the currently available experimental strategies, small interfering RNA (siRNA)-mediated gene silencing represents the most extensively investigated approach for evaluating the biological functions of STOML2. Across multiple tumour models, transient suppression of STOML2 has consistently resulted in reduced tumour cell proliferation, increased apoptosis, restoration of chemosensitivity and inhibition of oncogenic signalling pathways.
In cervical cancer, STOML2 overexpression was shown to activate the MEK/ERK signalling pathway, thereby promoting tumour cell proliferation, metastasis and resistance to cisplatin in HeLa and SiHa cells. STOML2 overexpression was achieved using an adenoviral expression vector (Ad-STOML2), whereas siRNA-mediated knockdown significantly enhanced cisplatin-induced cytotoxicity, reducing cell viability from approximately 85% to 41.6% in HeLa cells and 46.8% in SiHa cells (p < 0.01). In contrast, enforced STOML2 overexpression maintains cell viability at approximately 80% even in the presence of 10 μM cisplatin.
Mechanistically, loss of STOML2 increased mitochondrial Ca2+ accumulation, disrupted mitochondrial membrane potential, promoted cytochrome c release and activated caspase-3-dependent apoptosis. Pharmacological inhibition of MEK using U0126 abolished the protective effects of STOML2 overexpression, while siRNA-mediated silencing reduced MEK1/2 and ERK1/2 phosphorylation by approximately 60–70%. Collectively, these findings suggest that STOML2 contributes to cisplatin resistance by preserving mitochondrial integrity through activation of the MEK/ERK signalling pathway (Ref. Reference Hu, Zhang, Xu, Deng, Zhang, Kang and Liang130).
Similar observations have been reported in HNSCC, where STOML2 overexpression has been associated with activation of the IL-6–STAT3 signalling pathway and reduced sensitivity to cisplatin (Ref. Reference Qu, Jiang, Wang and Chen127). siRNA-mediated STOML2 knockdown significantly inhibited tumour cell proliferation, reduced colony formation by more than 50%, enhanced apoptosis and markedly increased cisplatin sensitivity. In SCC25 and SCC15 cells, STOML2 silencing reduced cisplatin IC₅₀ values from 17.08 μM to 4.16 μM and from 15.12 μM to 3.85 μM, respectively.
Clinical relevance was further supported by analysis of 91 HNSCC patient samples, in which 63% of tumours exhibited high STOML2 expression that significantly correlated with advanced T stage (P = 0.003), lymph-node metastasis (P = 0.009) and poorer overall survival (P = 0.0379). Molecular analyses demonstrated reduced IL-6 transcription, decreased STAT3 phosphorylation (Tyr705) and diminished STAT3 nuclear localisation following STOML2 knockdown, whereas exogenous IL-6 restored pathway activation. These findings indicate that STOML2 may promote chemoresistance, at least in part, through activation of the IL-6–STAT3 signalling axis (Ref. Reference Qu, Jiang, Wang and Chen127).
The relationship between STOML2 and therapeutic response appears to be more complex in pancreatic cancer, highlighting the context-dependent functions of this protein. In pancreatic ductal adenocarcinoma (PDAC), STOML2 overexpression has been shown to regulate mitochondrial quality control through interaction with PARL, thereby influencing mitophagy and the response to gemcitabine treatment (Ref. Reference Qin, Wang, Zhao, Li, Li, Yang, Zhao and Wang14).
Comprehensive functional analyses using PANC1 and BxPC3 cells, together with tissue microarray analysis of 79 paired PDAC specimens, demonstrated a positive correlation between STOML2 and PARL expression. Mechanistic studies employing MitoTracker staining, Seahorse metabolic analysis, co-immunoprecipitation and mitophagy assays revealed that STOML2 overexpression increased mitochondrial mass and respiratory activity while suppressing PINK1 accumulation and mitophagy. Rescue experiments combining STOML2 and PARL modulation further confirmed that STOML2 regulates mitochondrial homeostasis through PARL-dependent mechanisms.
Interestingly, unlike observations in several other tumour types, STOML2 overexpression enhanced gemcitabine-induced apoptosis and reduced tumour growth in xenograft models following gemcitabine treatment (Ref. Reference Qin, Wang, Zhao, Li, Li, Yang, Zhao and Wang14). These findings illustrate that the biological consequences of STOML2 modulation may differ substantially depending on tumour type and mitochondrial context, emphasising the importance of considering tumour-specific biology when evaluating STOML2 as a therapeutic target. This study therefore provides one of the clearest examples supporting the reviewers’ recommendation that context-dependent functions of STOML2 should be critically discussed rather than assuming a universal oncogenic mechanism.
An alternative therapeutic strategy has been explored in non-small cell lung cancer (NSCLC) through indirect suppression of STOML2 using the natural polyphenol resveratrol. Resveratrol-enhanced expression of miR-671-5p, which directly targets STOML2, thereby restoring paclitaxel sensitivity in resistant A549/PTX cells (Ref. Reference Kong, Zhang, Zhao, Zhao, Wang, Zhang, Tian and Ma143).
Combination treatment with resveratrol and paclitaxel significantly reduced cell viability, suppressed colony formation and increased apoptosis compared with paclitaxel alone. Molecular analyses demonstrated increased miR-671-5p expression together with reduced STOML2, PINK1 and Parkin expression, while luciferase reporter assays confirmed STOML2 as a direct miR-671-5p target. Transmission electron microscopy and autophagy marker analyses further demonstrated reduced autophagic activity following STOML2 suppression. Rescue experiments using STOML2 overexpression or PINK1 activation partially reversed these effects, supporting the conclusion that modulation of the miR-671-5p/STOML2/PINK1 axis contributes to restoration of chemosensitivity (Ref. Reference Kong, Zhang, Zhao, Zhao, Wang, Zhang, Tian and Ma143).
Collectively, these studies consistently demonstrate that siRNA-mediated suppression of STOML2 enhances chemosensitivity across multiple experimental cancer models through modulation of mitochondrial homeostasis, apoptosis and oncogenic signalling pathways. Nevertheless, several important limitations should be acknowledged. Most investigations rely on transient gene-silencing approaches performed in established cancer cell lines, with comparatively few studies evaluating long-term therapeutic efficacy in patient-derived models or genetically engineered animal systems. Furthermore, although restoration of chemosensitivity has been repeatedly observed, the molecular mechanisms underlying STOML2 function appear to vary among tumour types, suggesting that its biological role is highly context dependent. Consequently, while siRNA-mediated STOML2 inhibition provides compelling proof-of-concept for therapeutic targeting, substantial challenges related to delivery, target specificity, durability of gene silencing and clinical translation remain to be addressed before these approaches can be considered viable therapeutic strategies. Moreover, many of the available clinical studies involve relatively small retrospective patient cohorts, underscoring the need for larger multicentre prospective studies to validate STOML2 as a therapeutic target and biomarker.
shRNA-mediated knockdown and CRISPR/Cas9 gene editing of STOML2
Beyond transient siRNA-mediated suppression, stable gene silencing using short hairpin RNA (shRNA) and permanent gene disruption using CRISPR/Cas9 have provided valuable insights into the long-term biological functions of STOML2 in cancer progression and therapeutic resistance. Compared with siRNA approaches, these strategies permit prolonged suppression of STOML2 expression and therefore more accurately model its contribution to tumour growth, metastasis, mitochondrial remodelling and drug response. Collectively, these studies consistently demonstrate that sustained inhibition of STOML2 suppresses tumour progression and enhances responsiveness to multiple chemotherapeutic and targeted agents, although the underlying molecular mechanisms differ substantially among tumour types.
One of the earliest demonstrations of stable STOML2 inhibition was reported in colorectal cancer (CRC), where shRNA-mediated knockdown significantly reduced tumour growth and restored sensitivity to fluorouracil and sorafenib through inhibition of the PHB–MAPK signalling axis (Ref. Reference Ma, Chen, Xiong, Li, Xu, Wang, Wei, Mou, Wu, Cheng, Zou, Zhu, Zhou, Liu and Geng16). Stable suppression of STOML2 in SW620 cells, together with lentiviral overexpression in SW480 cells, demonstrated that STOML2 physically interacts with prohibitin (PHB), thereby promoting activation of RAF1, MEK1/2, and ERK1/2 signalling.
Clinical relevance was supported by tissue microarray analysis of 126 CRC specimens, in which elevated STOML2 expression correlated with advanced TNM stage (P = 0.002), lymph-node metastasis, and significantly shorter overall survival (median 38.6 versus 64.3 months; P < 0.001). Functionally, STOML2 silencing reduced cellular proliferation by approximately 40%, decreased colony formation by nearly 70%, induced G1-phase cell-cycle arrest, and markedly suppressed xenograft growth. These findings suggest that STOML2 contributes to colorectal cancer progression primarily through sustained activation of PHB-dependent MAPK signalling, although further studies are required to determine whether this interaction is conserved across other gastrointestinal malignancies (Ref. Reference Ma, Chen, Xiong, Li, Xu, Wang, Wei, Mou, Wu, Cheng, Zou, Zhu, Zhou, Liu and Geng16).
The largest body of evidence supporting STOML2 as a therapeutic target originates from hepatocellular carcinoma (HCC), where multiple independent studies have linked STOML2 with mitochondrial quality control, metastatic progression, oxidative stress responses, ferroptosis and therapeutic resistance.
One study demonstrated that shRNA-mediated STOML2 silencing enhanced mitophagy, reduced metastatic potential and restored sensitivity to lenvatinib and hydroxychloroquine in multiple HCC cell lines, including SMMC-7721, HCCLM3, Huh-7, Hep-G2 and SNU-387 cells (Ref. Reference Zheng, Huang, Lu, Yu, Zhao, Chen, Liu, Sun, Lin, Zheng, Chen and Zhang142). Stable suppression of STOML2 reduced proliferation by approximately 45%, migration by nearly 70% colony formation by approximately 55%, and decreased the lenvatinib IC₅₀ from 12.3 μM to 6.7 μM. These in vitro observations were supported by xenograft experiments showing marked reductions in tumour volume and pulmonary metastasis, while combination therapy with hydroxychloroquine further enhanced anti-tumour efficacy. Collectively, these findings suggest that STOML2 contributes to HCC progression by regulating mitochondrial quality control through the PINK1-mediated mitophagy pathway.
Additional evidence has linked STOML2 to the CYB5A–JAK/STAT signalling axis (Ref. Reference Guo, Liang, Wang, Zhou, Yin, Zhang, Wang, Wu, Ma, Liu, Sun, Ji, Li, Zhou, Yang, Guo, Cui, Li, Liu, Wang and Liu139). CYB5A expression was markedly reduced in HCC tissues and was associated with advanced AJCC stage, poor differentiation, elevated AFP levels and reduced overall survival. Mechanistically, CYB5A directly interacted with STOML2 and promoted its proteasomal degradation, thereby suppressing JAK1/STAT3 phosphorylation and reducing metastatic behaviour. Importantly, CYB5A-overexpressing tumours exhibited enhanced sensitivity to the JAK inhibitor ruxolitinib, suggesting that modulation of STOML2 stability may represent an alternative therapeutic strategy. Unlike direct STOML2 knockdown, this study highlights that regulation of STOML2 by upstream interacting proteins may also provide clinically relevant opportunities for therapeutic intervention.
Another independent investigation identified a distinct mechanism linking STOML2 to cell-cycle regulation and 5-fluorouracil resistance (Ref. Reference Li, Zheng, Yu, Hou, Cui, Yin, Zhou, Sun, Zhang and Huang144). Stable modulation of STOML2 expression demonstrated that overexpression promoted cell-cycle progression through activation of the c-MYC/Cyclin D1/CDK4 pathway while suppressing p21 expression.
Functional analyses further revealed significantly reduced sensitivity to 5-fluorouracil in STOML2-overexpressing cells, whereas shRNA-mediated knockdown restored chemosensitivity. Bioinformatic analyses of TCGA-HCC datasets additionally identified enrichment of pathways involved in DNA replication, chromosome segregation and xenobiotic metabolism among tumours expressing high STOML2 levels. These observations suggest that STOML2 contributes not only to mitochondrial adaptation but also to cell-cycle reprogramming and metabolic mechanisms associated with chemoresistance.
The application of CRISPR/Cas9 genome editing has further expanded the understanding of STOML2-associated signalling networks. Rather than directly deleting STOML2, one recent study targeted RAB-interacting factor (RABIF), an upstream regulator that interacts with STOML2 to coordinate mitophagy and metabolic reprogramming (Ref. Reference Feng, Zhang, Wen, Wang, Zhang, Zheng, Zhang and Liu145). CRISPR-mediated RABIF knockout impaired mitochondrial respiration, glycolysis and mitophagy while significantly increasing sorafenib sensitivity in HCC models. Rescue experiments demonstrated that disruption of the RABIF–STOML2 axis reduced tumour growth both in vitro and in xenograft models. These findings emphasise that STOML2 functions within a broader mitochondrial regulatory network rather than acting as an isolated signalling molecule, suggesting that indirect targeting of STOML2-associated protein complexes may represent an alternative therapeutic strategy.
Recent work has also identified STOML2 as an important regulator of ferroptosis resistance through activation of the AKT–SLC7A11 pathway (Ref. Reference Yu, Tao, Han, Zhang, Yu, Zheng, Li and Huang146). Increased STOML2 expression correlated with sorafenib resistance in both patient samples and experimental HCC models. Functional analyses demonstrated that STOML2 knockdown suppressed AKT activation, reduced SLC7A11 expression, increased ROS accumulation and enhanced ferroptotic cell death following sorafenib treatment. Pharmacological activation of AKT restored SLC7A11 expression and partially rescued the effects of STOML2 knockdown, whereas inhibition of AKT reversed the protective effects of STOML2 overexpression. These findings identify ferroptosis regulation as an additional mechanism through which STOML2 may contribute to therapeutic resistance, expanding its functional role beyond mitochondrial dynamics and mitophagy alone.
Studies employing shRNA-mediated gene silencing and CRISPR/Cas9-based approaches consistently support an important role for STOML2 in tumour progression, metastatic dissemination, mitochondrial homeostasis and therapeutic resistance. Nevertheless, these investigations also highlight that the biological functions of STOML2 are highly tumour dependent. In colorectal cancer, STOML2 predominantly regulates PHB-dependent MAPK signalling, whereas hepatocellular carcinoma studies have identified distinct mechanisms involving mitophagy, JAK/STAT signalling, cell-cycle regulation, ferroptosis and metabolic reprogramming. These observations suggest that STOML2 should not be regarded as a universal regulator of chemoresistance but rather as a mitochondrial scaffold protein whose downstream effects are determined by tissue-specific interacting partners, including PHB, PARL, CYB5A, RABIF and components of the AKT–SLC7A11 axis. Furthermore, despite consistently encouraging preclinical findings, nearly all available evidence has been generated using established cancer cell lines, xenograft models or retrospective patient cohorts. Consequently, validation in patient-derived organoids, genetically engineered mouse models and prospective clinical studies will be essential before STOML2-directed therapeutic strategies can be translated into routine clinical oncology.
Emerging therapeutic strategies and translational challenges
Although genetic suppression of STOML2 through siRNA, shRNA and CRISPR/Cas9 approaches has demonstrated promising antitumor activity in preclinical studies, translation into clinical practice remains challenging. At present, no clinically approved therapies directly target STOML2, largely because STOML2 is a mitochondrial scaffold protein for which validated enzymatic activity or experimentally established druggable ligand-binding pockets have not yet been identified. Furthermore, the absence of experimentally resolved high-resolution structural information for full-length STOML2 limits structure-based drug discovery and rational inhibitor design. Consequently, current therapeutic strategies remain focused primarily on modulation of STOML2 expression rather than direct pharmacological inhibition (Ref. Reference Christie, Lemke, Elias, Chau, Kirchhof, Li, Ball, Dunn, Hatch and Madrenas35).
Targeting mitochondrial proteins presents additional challenges because many are essential for mitochondrial homeostasis, OXPHOS and cellular energy metabolism, making selective inhibition difficult. Therapeutic agents must also overcome delivery barriers, including cellular uptake, intracellular trafficking and efficient delivery to the mitochondrial compartment (Ref. Reference Khan, Waseem, Zehra, Aiman, Bhardwaj, Ansari, Hassan and Islam149). These challenges raise important toxicity concerns because systemic disruption of mitochondrial function may affect normal, highly energy-dependent tissues and cause metabolic dysfunction or impaired OXPHOS. Therefore, tumour-selective targeting while preserving mitochondrial function in normal tissues will be critical for achieving an acceptable therapeutic window (Ref. Reference Wang, Guo, Kuang, Hou and Liu150).
RNA-based therapeutics represent promising approaches for modulating STOML2 expression. Small interfering siRNAs, shRNAs, antisense oligonucleotides (ASOs) and microRNA-based therapeutics can reduce target gene expression with high specificity. Among these, siRNA-mediated knockdown has shown consistent restoration of chemosensitivity across several experimental cancer models. However, RNA therapeutics remain limited by nuclease degradation, poor cellular uptake, innate immune activation, off-target effects and limited penetration into solid tumours (Ref. Reference Wang, Lu, Wientjes and Au151). These limitations have stimulated interest in advanced delivery platforms, including lipid nanoparticles (LNPs), exosome-based carriers and mitochondrial-targeting systems such as triphenylphosphonium (TPP)-conjugated nanoparticles, mitochondria-penetrating peptides (MPPs) and MitoPorter systems. Although such platforms have shown encouraging results for other mitochondrial targets, their application to STOML2 remains largely unexplored (Ref. Reference Shajari, Mansoori, Davudian, Mohammadi and Baradaran152).
Gene-editing technologies such as CRISPR/Cas9 offer the possibility of permanent STOML2 inhibition and have provided valuable mechanistic insights into mitochondrial regulation and chemoresistance. However, clinical implementation remains constrained by inefficient in vivo delivery, potential off-target genome editing, immunogenicity associated with Cas proteins, tumour heterogeneity and ethical considerations related to permanent genomic modification. Consequently, CRISPR-based approaches are currently more suitable as research tools for functional validation than as immediate therapeutic strategies (Ref. Reference Rasul, Hussen, Salihi, Ismael, Jalal, Zanichelli, Jamali, Baniahmad, Ghafouri-Fard, Basiri and Taheri153).
The context-dependent functions of STOML2 also present an important consideration for therapeutic development. STOML2-associated mechanisms differ among tumour types, including PHB–MAPK signalling in colorectal cancer (Ref. Reference Ma, Chen, Xiong, Li, Xu, Wang, Wei, Mou, Wu, Cheng, Zou, Zhu, Zhou, Liu and Geng16), PARL–PINK1-mediated mitophagy in pancreatic cancer (Ref. Reference Qin, Wang, Zhao, Li, Li, Yang, Zhao and Wang14), IL-6–JAK/STAT signalling in HNSCC (Ref. Reference Qu, Jiang, Wang and Chen127) and so forth. These observations suggest that STOML2-directed therapies may need to be tailored according to tumour-specific molecular contexts rather than applied universally. Biomarker-guided patient stratification and comprehensive molecular profiling may therefore improve therapeutic efficacy while minimising unnecessary treatment.
Future clinical translation will depend on integrating multi-omics, single-cell and spatial transcriptomics, AI-assisted drug discovery and patient-derived organoid models to define tumour-specific dependencies on STOML2. High-resolution structural studies using cryo-electron microscopy and advanced computational modelling may further facilitate selective inhibitor development. Combining STOML2-directed strategies with chemotherapy, targeted agents, immunotherapy or ferroptosis-inducing compounds may also provide therapeutic benefit by simultaneously disrupting mitochondrial adaptation and oncogenic signalling.
Collectively, STOML2-targeting strategies have distinct advantages and limitations. RNA-based approaches currently provide practical means of modulating STOML2 expression but remain limited by delivery and specificity. CRISPR/Cas9 enables permanent gene disruption and is valuable for mechanistic studies, although delivery and long-term safety concerns restrict clinical application. Indirect pharmacological approaches may offer greater translational feasibility by targeting STOML2-associated pathways, but they lack specificity for STOML2 itself. Overall, current evidence remains largely preclinical and further validation of tumour specificity, therapeutic efficacy, delivery and long-term safety is required before STOML2-directed therapies can progress towards clinical application.
Conclusion
STOML2 is an important mitochondrial protein that helps maintain mitochondrial structure and function by supporting cardiolipin synthesis and stabilising the IMM. By regulating key cell survival and proliferative signalling pathways, including MAPK/ERK, IL-6–JAK/STAT3 and PINK1–Parkin, while facilitating cellular adaptation to stress through the modulation of mitochondrial dynamics, STOML2 has emerged as a key regulator of cancer progression and chemoresistance. Elevated STOML2 expression has been consistently associated with aggressive tumour behaviour, metastasis, poor patient survival and resistance to chemotherapy, underscoring its potential importance in cancer biology.
Despite these advances, several critical questions remain unanswered. The precise structure of STOML2 has not yet been fully resolved, limiting our understanding of its interactions with mitochondrial proteins and the molecular mechanisms through which it regulates cancer-associated processes. Additionally, further in vivo studies are required to validate the biological role of STOML2 and assess its potential as a therapeutic target. Another promising but underexplored area is the evaluation of STOML2 as a biomarker for identifying patients who may exhibit differential responses to specific therapeutic interventions.
Overall, although current research establishes STOML2 as a central regulator of mitochondrial homeostasis, cancer cell metabolism and therapeutic resistance, much remains to be elucidated regarding its biological functions and clinical applications. A deeper understanding of its structure, molecular mechanisms and druggability could facilitate the development of novel therapeutic strategies and improve precision cancer treatment. By comprehensively examining the role of STOML2 in cancer progression and the development of chemoresistance, this review highlights its potential as both a therapeutic target and a biomarker, while proposing an integrated model of the consequences of STOML2 inhibition as illustrated in Figure 5.
Hypothesised model of the potential consequences of STOML2 inhibition. The schematic presents a proposed model, developed from the overall concepts discussed in this review, illustrating the potential effects of STOML2 inhibition on (A) cell-survival and proliferation-associated pathways, potentially reducing cell division and metastatic potential and (B) mitochondrial dynamics, including increased fission and reduced fusion. These alterations may enhance chemosensitivity and promote mitophagy and oxidative stress, ultimately contributing to cancer cell death.
Figure 5. Long description
On the far left, blue spheres representing S T O M L 2 Inhibitor target the S T O M L 2 protein on a mitochondrial membrane. Two large curved arrows lead from this interaction to two distinct panels on the right.
Top Panel: Compromised cell survival pathways. A central box labeled Cell Proliferation / Survival / Metastasis is surrounded by ten circular pathway labels: J A K - S T A T, P I 3 K - A K T, M A P K, Wnt / beta-Catenin, Notch, T G F - beta / S M A D, Hedgehog, Hippo, p 5 3, and N F - kappa B. An arrow points from this panel to the text Cell Division with a red downward arrow, indicating a decrease.
Bottom Panel: Altered mitochondrial dynamics.
- On the left side, the label Fission with a red upward arrow shows D R P 1, M F F, and F I S 1 proteins promoting the breaking apart of mitochondria.
- On the right side, the label Fusion with a red downward arrow shows O P A 1, M F N 2, and M F N 1 proteins failing to join mitochondria.
- Both processes lead to a central Mitophagy event.
- Below this, three jagged red shapes labeled R O S (Reactive Oxygen Species) indicate oxidative stress.
- Arrows from this panel point to Chemosensitivity with a red upward arrow and Improved Cell Death.
Abbreviations
- CRC
-
colorectal cancer
- CSC
-
cancer stem cells
- DDR
-
DNA damage response
- DRP1
-
dynamin-related protein 1
- EMT
-
epithelial–mesenchymal transition
- HCC
-
hepatocellular carcinoma
- HNSCC
-
head and neck squamous cell carcinoma
- MFN2
-
mitofusin-2
- OPA1
-
optic atrophy 1
- OXPHOS
-
oxidative phosphorylation
- PARL
-
presenilin-associated rhomboid-like protein
- PHB
-
prohibitin
- PINK1
-
PTEN-induced putative kinase 1
- ROS
-
reactive oxygen species
- STOML2
-
stomatin-like protein 2
Acknowledgements
The authors would like to acknowledge the support and facilities provided by Jaypee Institute of Information Technology, Sector 62, Noida.
Author Contribution
Writing (original draft), Data Curation, Resources: V.S.; Review and editing, Supervision, Resources, Conceptualisation: S.M.; Review and editing: D.K.S.; Review and editing, Supervision: K.K.S.
Funding statement
This research received no external funding.
Competing Interests
The authors declare no competing interest.
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