Pathogenesis of hepatic fibrosis

Fibrosis is a conserved wound-healing and tissue repair response that occurs across multiple organ systems. However, when injury is chronic or repair mechanisms become dysregulated, fibrosis can become pathological and lead to progressive organ dysfunction. In the liver, hepatic fibrosis commonly arises from chronic insults such as viral hepatitis, alcohol use or metabolic dysfunction-associated steatotic liver disease (MASLD), leading to excessive ECM accumulation that disrupts hepatic architecture and impedes blood and bile flow (Ref. Reference Kisseleva and Brenner38). Prolonged hepatic fibrosis culminates in cirrhosis, which ranks as the eleventh leading cause of death globally (Ref. Reference Shahzad, Bokhari, Rabia, Khan, Ali, Hashim, Shahzad, Tariq, Barkat-Ullah, Rasheed, Niazi, Hassan, Khan, Awan, Waqas and Ahmed39). Hepatic stellate cells (HSCs) occupy a central role in liver fibrogenesis: quiescent HSCs reside in the Space of Disse and store retinyl esters, but upon activation by reactive oxygen species, inflammatory cytokines or TGF-β, they transdifferentiate into myofibroblasts that secrete excessive collagen and ECM proteins, thereby driving fibrotic remodelling (Ref. Reference Khomich, Ivanov and Bartosch40).

Role of adiponectin in hepatic fibrosis

Numerous studies have demonstrated that low circulating adiponectin levels are associated with the development and progression of Nonalcoholic fatty liver diseases (NAFLD) and Nonalcoholic steatohepatitis (NASH) (Refs Reference Polyzos, Toulis, Goulis, Zavos and Kountouras41, Reference Zhang, Niu, Gu, Lu, Zhang, Li, Yang, Qin and Su42, Reference Micu, Amzolini, Abu-Alhija, Forţofoiu, Vladu, Clenciu, Mitrea, Mogoantă, Crişan, Predescu and Radu43). Quantification of serum adiponectin in patients with different degrees of NAFLD concluded that lower levels were associated with early fibrosis and worse inflammation (Ref. Reference Finelli and Tarantino44). These clinical findings have been corroborated in animal models: adiponectin-deficient mice fed a high-fat diet are more susceptible to developing hepatic steatosis and metabolic dysfunction compared to wild-type controls (Ref. Reference Moyce Gruber, Cole, Xiang, Fonseca, Klein, Hatch, Doucette and Dolinsky45). A recent study generated HSC-specific adiponectin overexpression and null mouse models, demonstrating that HSC-specific adiponectin overexpression reduces liver fibrosis, whereas HSC-specific adiponectin elimination accelerates fibrosis progression, identifying a local adiponectin-PPARγ axis in HSCs that operates independently of circulating adiponectin (Ref. Reference Zhao, Zhu, Lee, Funcke, Zhang, Wang, Lin, Field, Sun, Li, Ekane, Onodera, Li, Zhu, Kusminski, Hinds and Scherer46).

Mechanistically, adiponectin reduces TGF-β action in activated HSCs via AMPK-dependent signalling (Ref. Reference Adachi and Brenner47). HSCs treated with adiponectin exhibit lower degrees of activation, and adiponectin-activated AMPK signalling in HSCs antagonises TGF-β signalling, ultimately suppressing fibrogenesis (Refs Reference Kumar, Raeman, Chopyk, Smith, Verma, Liu and Anania48, Reference Lim, Oh, Kim, Sohn and Park49). Additionally, adiponectin inhibits the TLR-4 signalling pathway in Kupffer cells, the resident macrophages of the liver, thereby preventing HSC proliferation and migration (Ref. Reference Ramezani-Moghadam, Wang, Ho, Iseli, Alzahrani, Xu, van der Poorten, Qiao, George and Hebbard50). Studies using adiponectin knockout mice demonstrated that adiponectin deficiency enhanced NF-κB signalling in Kupffer cells and increased the secretion of pro-inflammatory cytokines, including TNF-α and IL-6, whereas adiponectin treatment suppressed inflammatory signalling and exerted anti-inflammatory effects in these cells (Refs Reference Matsumoto, Tamura, Kamada, Kiso, Fukushima, Wada, Maeda, Kihara, Funahashi, Matsuzawa, Shimomura and Hayashi51–Reference Liu, Tao, Sun, Wu, Yang, Jian, Peng, Hu, Liu and Liu54). Together, these findings demonstrate that adiponectin suppresses pro-inflammatory and profibrotic signalling in both HSCs and Kupffer cells, positioning it as a key protective factor against hepatic fibrosis.

Pathogenesis of pulmonary fibrosis

Similar to hepatic fibrosis, pulmonary fibrosis is characterised by excessive ECM accumulation and progressive tissue remodelling (Ref. Reference Wang, Li, Hao, Li, Zhu, Yu and Chen55). In the lung, fibrotic changes primarily affect the alveolar walls, leading to thickening and stiffening of the pulmonary interstitium, disruption of normal alveolar architecture and impaired gas exchange (Refs Reference Plantier, Cazes, Dinh-Xuan, Bancal, Marchand-Adam and Crestani56, Reference He, He, Chen, Li and Cao57). As fibrosis progresses, reduced pulmonary compliance and impaired alveolar ventilation compromise oxygen uptake and carbon dioxide elimination, ultimately resulting in respiratory insufficiency (Ref. Reference Plantier, Cazes, Dinh-Xuan, Bancal, Marchand-Adam and Crestani56). Idiopathic pulmonary fibrosis (IPF), the most extensively studied fibrotic lung disease, exemplifies these pathological changes and is associated with a poor prognosis, with a median survival of only 3–5 years following diagnosis (Ref. Reference Senhaji, Senhaji, Abbassi, Karhate, Serraj, el Biaze, Benjelloun, Ouldim, Bouguenouch and Amara58).

Role of adiponectin in pulmonary fibrosis

Circulating adiponectin levels are reduced in patients with IPF and are inversely associated with the extent of pulmonary fibrosis, and adiponectin has been proposed as a potential prognostic biomarker for fibrotic interstitial lung diseases (Ref. Reference Huang, Gong, Wu, Shi and Liang59). In chronic obstructive pulmonary disease (COPD), a mouse model established by tobacco smoke exposure demonstrated increased adiponectin production in bronchoalveolar lavage fluid and airway epithelial cells, an observation that, while initially paradoxical, likely reflects an adaptive compensatory response to counteract inflammation (Ref. Reference Siriphorn, Thorsuwan, Thongam, Ruangklai, Hussarin, Rungruang and Srisuma60).

Adiponectin exerts antifibrotic effects in the lungs through multiple mechanisms. Treatment with adiponectin inhibited EMT in alveolar epithelial cells, thereby preserving the epithelial phenotype and preventing transformation into collagen-secreting cells (Ref. Reference Cui, Guo, Shen, Yu, Gu, Mao and Wang61). In a bleomycin-induced model of lung fibrosis, adiponectin treatment reduced α-SMA expression and type I collagen deposition. Further in vitro analyses demonstrated that adiponectin altered fibroblast signalling by shifting TGF-β pathways toward a less fibrogenic phenotype (Ref. Reference Wang, Yang, Wu, Tong, Zhu, Cai, Wan and Zhang62). The study also showed that adiponectin inhibited NF-κB-mediated activation of lung fibroblasts, thereby attenuating inflammation-driven fibrotic responses. Collectively, these data support adiponectin as an endogenous antifibrotic mediator in the lungs that operates through suppression of EMT, myofibroblast differentiation and inflammatory signalling.

Pathogenesis of cardiac fibrosis

In the heart, fibrosis contributes to both structural and functional remodelling of the myocardium (Ref. Reference Talman and Ruskoaho63). Although cardiomyocytes account for the majority of myocardial volume, cardiac fibroblasts represent a substantial proportion of cardiac cells, comprising approximately 20%–60% of the total cardiac cell population by number, with their abundance increasing during development, ageing and disease (Ref. Reference Pinto, Ilinykh, Ivey, Kuwabara, D’Antoni, Debuque, Chandran, Wang, Arora, Rosenthal and Tallquist64). As the primary resident mesenchymal cells of the myocardium, cardiac fibroblasts are responsible for maintaining ECM homeostasis, which provides structural support to cardiac tissue and regulates cellular communication, mechanical signalling and tissue integrity (Ref. Reference Bowers, Meng and Molkentin65). Consequently, alterations in ECM composition or turnover can adversely affect cardiac function by increasing myocardial stiffness and impairing contractile performance (Refs Reference Silva, Pereira, Fonseca, Pinto-do-Ó and Nascimento66–Reference Faleeva, Ahmad, Theofilatos, Lynham, Watson, Whitehead, Marhuenda, Iskratsch, Cox and Shanahan69). Following cardiac injury, including mechanical stress, pressure overload associated with hypertension or ischaemic injury after myocardial infarction, cardiac fibroblasts become activated and differentiate into myofibroblasts (Refs Reference Garvin and Katwa70–Reference Xia, Lee, Li, Corbett, Mendoza and Frangogiannis73). Initially, this response serves a reparative role by preserving structural integrity and facilitating wound healing. However, persistent injury leads to excessive ECM accumulation by myofibroblasts that promotes maladaptive interstitial and replacement fibrosis, ultimately contributing to adverse cardiac remodelling, impaired ventricular function, and heart failure (Ref. Reference Van Linthout, Matz, González and Davis74).

Role of adiponectin in cardiac fibrosis

Low levels of circulating adiponectin are consistently associated with increased cardiac fibrosis and adverse remodelling across multiple cardiovascular pathologies. In ischaemic heart disease, hypoadiponectinemia results in worsened inflammation and collagen accumulation, further compromising the function of the infarcted heart (Ref. Reference Yue, Zhang, Chang, Zhao, Wang and Li75). A prospective human study further found that hypoadiponectinemia itself is an independent risk factor for the development of hypertension (Ref. Reference Imatoh, Miyazaki, Momose, Tanihara and Une76). In diabetic cardiomyopathy, characterised by metabolic dysfunction and low adiponectin levels, restoration of adiponectin signalling stabilises energy homeostasis and reduces cell death (Refs Reference Zuo, Xiao, Qiu, Liu, Zhang and Zhou77, Reference Kim, Lim, Kim, Hong, Park, Chung, Choi, Kim, Park, Kim and Park78). In heart failure, low adiponectin levels are associated with cardiac hypertrophy and increased fibrosis; in an aldosterone-induced model of heart failure, adiponectin transgenic mice had improved left ventricular function despite hypertrophy compared to wild-type mice (Ref. Reference Tanaka, Wilson, Essick, Duffen, Scherer, Ouchi and Sam79). In a murine model of angiotensin II-induced hypertensive heart disease, adiponectin knockout mice developed more severe cardiac fibrosis and inflammation than wild-type controls, accompanied by upregulation of collagen I, α-SMA, IL-1β and TNF-α (Ref. Reference Qi, Jia, Li, Li and Du36). They showed that adiponectin activated autophagy in macrophages and inhibited NFκB signalling and that it increased secretion of anti-inflammatory cytokines including IL-10 through the AMPK pathway, overall reducing the extent of cardiac fibrosis. Together, these studies suggest that adiponectin mitigates cardiac fibrosis through coordinated regulation of inflammatory, metabolic and profibrotic signalling pathways.

Pathogenesis of renal fibrosis

Renal fibrosis is a hallmark feature of chronic kidney disease (CKD) and represents the final common pathway leading to progressive loss of kidney function and ultimately end-stage renal disease (ESRD) (Ref. Reference Lee, Kim and Choi80). Despite the diverse etiologies of CKD, including diabetic nephropathy, glomerulonephritis and obstructive nephropathy, these conditions converge on shared fibrogenic mechanisms characterised by persistent inflammation, activation of fibroblasts and myofibroblasts and excessive deposition of ECM proteins (Ref. Reference Panizo, Martínez-Arias, Alonso-Montes, Cannata, Martín-Carro, Fernández-Martín, Naves-Díaz, Carrillo-López and Cannata-Andía81). In addition, renal mesangial cells, specialised structural cells within the glomerulus, contribute significantly to disease progression. Following kidney injury, particularly in conditions such as diabetes and lupus nephritis, mesangial cells become activated and undergo excessive proliferation, leading to increased production of ECM proteins and pro-inflammatory cytokines that promote glomerulosclerosis and fibrotic remodelling (Ref. Reference Zhao82). The resulting tubulointerstitial fibrosis and glomerulosclerosis disrupt normal renal architecture, impair nephron function and contribute to the irreversible decline in kidney function (Ref. Reference Liu, Quinn, Lam, al-Wahsh, Sood, Tangri, Tonelli and Ravani83).

Role of adiponectin in renal fibrosis

Reduced adiponectin levels have been associated with increased renal fibrosis and loss of kidney function in both CKD and diabetic nephropathy. In diabetic nephropathy, hypoadiponectinaemia causes increased mesangial cell expansion and ECM accumulation within glomeruli (Ref. Reference Fang, Bae, Hu, Liu, Zhou, Williams, Maksimowski, Lu, Konvalinka, John and Scholey84). In a mouse model of kidney disease, adiponectin deficiency resulted in worsened glomerular hypertrophy, fibrosis and overall kidney function, with elevated levels of TNFα, TGF-β and collagen. Restoration of adiponectin via adenoviral delivery improved overall kidney function and decreased inflammatory and fibrotic markers (Ref. Reference Ohashi, Iwatani, Kihara, Nakagawa, Komura, Fujita, Maeda, Nishida, Katsube, Shimomura, Ito and Funahashi85). Adiponectin can also inhibit synthesis of ECM components in mesangial cells, slowing the progression of renal fibrosis (Ref. Reference Tan, Tang and Rui32).

Adiponectin modulates renal fibrotic pathways through several complementary mechanisms. It suppresses TGF-β signalling and EMT in renal epithelial cells, thereby preventing renal fibrosis in hypertensive mice (Ref. Reference Li, Song, Ruan, Xue and Zhao86). In glomerular tissue, adiponectin mitigates mesangial cell expansion via AMPK signalling; using human mesangial cells, it was shown that adiponectin prevented PDGF-induced mesangial cell expansion through an AMPK–mTOR pathway (Ref. Reference Su, Deng, Zhang, Long and Peng34). By curtailing TGF-β signalling, inhibiting mesangial cell expansion and stabilising epithelial cells, adiponectin modulates the fibrotic remodelling that characterises CKD and diabetic nephropathy.

Pathogenesis of skeletal muscle fibrosis

In skeletal muscle, fibrosis is a prominent pathological feature of disorders such as Duchenne muscular dystrophy (DMD) (Ref. Reference Zhou and Lu87). Excessive deposition of ECM components, particularly collagen, progressively replaces functional muscle tissue, disrupting normal muscle architecture and reducing tissue elasticity (Ref. Reference Gong, Xu, Zhang, Shen, Sun and Chen88). This pathological accumulation of ECM impairs force transmission, limits muscle regeneration by creating a hostile microenvironment for satellite cells and restricts nutrient and oxygen diffusion (Ref. Reference Awad, Aguirre, Adegbite, Sajeev Kumar, Yacoub, Xia and Brotto89). Consequently, skeletal muscle fibrosis contributes directly to muscle weakness, loss of contractile function and progressive functional decline observed in DMD and other chronic muscle disorders (Ref. Reference Zhou and Lu87).

Role of adiponectin in skeletal muscle fibrosis

Emerging evidence suggests that low adiponectin levels may contribute to the progression of skeletal muscle fibrosis and exacerbate the dystrophic phenotype in DMD (Ref. Reference Zelikovich, Quattrocelli, Salamone, Kuntz and McNally90). In the mdx mouse model of DMD, adiponectin deficiency was associated with decreased muscle strength, increased muscle damage and heightened inflammatory responses (Ref. Reference Zelikovich, Quattrocelli, Salamone, Kuntz and McNally90). Conversely, adiponectin administration attenuated disease severity by reducing the expression of pro-inflammatory mediators and suppressing NF-κB activity, while simultaneously promoting the expression of myogenic markers involved in muscle repair and regeneration (Ref. Reference Abou-Samra, Boursereau, Lecompte, Noel and Brichard91). Similarly, studies using the D2.mdx mouse model demonstrated that activation of adiponectin signalling mitigated early diaphragm fibrosis through the AMPK–PGC-1α pathway, leading to inhibition of both NF-κB-mediated inflammation and TGF-β-driven fibrotic signalling (Refs Reference Bellissimo, Gandhi, Castellani, Murugathasan, Delfinis, Thuhan, Garibotti, Seo, Rebalka, Hsu, Sweeney, Hawke, Abdul-Sater and Perry92, Reference Dubuisson, Versele, Davis-López de Carrizosa, Selvais, Noel, Planchon, van den Bergh, Brichard and Abou-Samra93). Given the central roles of chronic inflammation and excessive ECM deposition in DMD progression, these findings highlight adiponectin as a key regulator of muscle homeostasis and suggest that adiponectin-based therapies may represent a promising strategy for limiting fibrosis and preserving muscle function, particularly during the early stages of disease development.

Pathogenesis of skin fibrosis in systemic sclerosis

Fibrosis also plays a central role in autoimmune conditions such as systemic sclerosis (scleroderma; SSc), a chronic multisystem autoimmune disease. The pathogenesis of SSc is complex and involves an interplay between vascular injury, inflammation and fibrotic remodelling (Ref. Reference Asano94). Early endothelial cell damage triggers activation of both innate and adaptive immune responses, leading to the production of cytokines, chemokines and autoantibodies that promote fibroblast activation (Refs Reference Quan95, Reference Shao, Saredy, Yang, Sun, Lu, Saaoud, Drummer, Johnson, Xu, Jiang, Wang and Yang96). Activated fibroblasts subsequently differentiate into myofibroblasts, which secrete excessive amounts of collagen and other ECM components, resulting in progressive thickening, stiffening and loss of elasticity of the skin and connective tissues (Ref. Reference Wang, Wen, Xu, Zhao, Jiang, Yuan, Zhang, Gao and Li97). Although cutaneous fibrosis is a defining feature of SSc, fibrotic remodelling frequently extends to internal organs, including the lungs, heart, kidneys and gastrointestinal tract, where it contributes significantly to disease morbidity and mortality (Ref. Reference Sobolewski, Maślińska, Wieczorek, Łagun, Malewska, Roszkiewicz, Nitskovich, Szymańska and Walecka98).

Role of adiponectin in skin fibrosis

In SSc, circulating adiponectin levels are frequently reduced and exhibit an inverse correlation with the severity of skin fibrosis in affected patients (Ref. Reference Leodori, Pellicano, Basile, Colalillo, Navarini, Gigante, Gulli, Marino, Basile and Rosato99). Experimental studies have demonstrated that adiponectin-deficient mice develop an exaggerated dermal fibrotic response, whereas transgenic mice with constitutively elevated adiponectin levels are protected against both skin and peritoneal fibrosis and exhibit expansion of dermal white adipose tissue (Ref. Reference Marangoni, Masui, Fang, Korman, Lord, Lee, Lakota, Wei, Scherer, Otvos, Yamauchi, Kubota, Kadowaki, Asano, Sato, Tourtellotte and Varga100). Using a murine model of SSc, it was shown that the adiponectin signalling improved dermal fibrosis via attenuated fibroblast activation and inhibition of EMT (Ref. Reference Yamashita, Lakota, Taniguchi, Yoshizaki, Sato, Hong, Zhou, Sodin-Semrl, Fang, Asano and Varga101). Furthermore, in vitro studies revealed that adiponectin counteracted the profibrotic effects of TGF-β in cultured fibroblasts and reduced fibrotic responses in three-dimensional human skin equivalents, partly through inhibition of focal adhesion kinase (FAK) signalling, a cytoplasmic tyrosine kinase that acts as a central hub linking extracellular matrix-derived mechanical signals to intracellular profibrotic pathways (Ref. Reference Yamashita, Lakota, Taniguchi, Yoshizaki, Sato, Hong, Zhou, Sodin-Semrl, Fang, Asano and Varga101). Collectively, these findings identify dysregulated adiponectin signalling as an important contributor to skin fibrosis and highlight the therapeutic potential of restoring adiponectin activity as a novel strategy for the treatment of SSc.

Fibrosis as a hallmark of ageing

Beyond organ-specific and autoimmune disorders, fibrosis is increasingly recognised as an important feature of biological ageing and a common contributor to age-related organ dysfunction. In recent years, the term ‘fibroageing’ has been proposed to describe the increased propensity for fibrosis associated with ageing (Ref. Reference Selman and Pardo102). Central to this concept is the ECM, which undergoes age-related modifications including glycation, crosslinking and accumulation, resulting in increased matrix stiffness (Ref. Reference Boaru, de Leon-Oliva, de Castro-Martinez, Garcia-Montero, Fraile-Martinez, García-González, Pérez-González, Alhaddadin, Barrena-Blázquez, Lopez-Gonzalez, de la Torre, Pekarek, Saez, Ríos-Espinosa, Pekarek, de la Sacristana, Hernández-Fernández, Casanova, Castel-Oñate, Garcia-Honduvilla, Buján, Diaz-Pedrero, Alvarez-Mon and Ortega103). These alterations not only disrupt normal tissue architecture and function but also reinforce profibrotic signalling through positive feedback mechanisms, further promoting ECM deposition. Furthermore, increased matrix stiffness has been implicated in several hallmarks of ageing, including cellular senescence and mitochondrial dysfunction, suggesting that ECM remodelling may represent a key mechanistic link between ageing, fibrosis and age-associated tissue decline (Ref. Reference Selman and Pardo102).

Role of adiponectin in age-associated fibrosis

Given its role in mitigating fibrosis, adiponectin has garnered considerable interest as a therapeutic target for age-related diseases. In a mouse model of ageing combined with high-fat diet feeding, adiponectin knockout mice displayed accelerated ageing, worse glucose and lipid metabolism and shorter lifespan on both chow and high-fat diet. In contrast, adiponectin transgenic mice had improved metabolism, less age-related inflammation and fibrosis and enhanced lifespan (Ref. Reference Li, Zhao, Zhang, Zhu, Gliniak, Vishvanath, An, Wang, Deng, Zhu, Shan, Sherwood, Onodera, Oz, Gordillo, Gupta, Liu, Horvath, Dixit and Scherer104). In geriatric mdx mice (14 months of age), AdipoRon treatment reversed cardiac fibrosis, hypertrophy and oxidative stress through activation of the AdipoR1/CaMKK2/AMPK signalling axis (Ref. Reference Abou-Samra, Dubuisson, Marino, Selvais, Romain, Davis-López de Carrizosa, Noel, Beauloye, Brichard and Horman105). Similarly, chronic AdipoRon administration in aged wild-type mice improved skeletal muscle function and enhanced mitochondrial capacity via AMPK/PGC-1α activation (Ref. Reference Balasubramanian, Schaar, Gustafson, Smith, Howell, Greenman, Baum, Colman, Lamming, Diffee and Anderson106). Collectively, these findings demonstrate that pharmacological activation of adiponectin receptors may help preserve tissue homeostasis, prevent age-related fibrosis and improve overall healthspan and lifespan.

Collectively, the evidence reviewed across hepatic, pulmonary, cardiac, renal, cutaneous, skeletal muscle and age-associated fibrosis indicates that adiponectin exerts broadly conserved antifibrotic effects despite the diverse cellular and molecular mechanisms underlying fibrosis in different tissues. Across organ systems, adiponectin consistently suppresses fibroblast and myofibroblast activation, attenuates TGF-β-mediated profibrotic signalling, reduces inflammation and oxidative stress and limits pathological ECM deposition. These findings support the concept that adiponectin functions as a key endogenous regulator of tissue remodelling and fibrosis. The consistent protective effects observed in both experimental and preclinical models highlight the therapeutic potential of targeting adiponectin signalling pathways, providing a strong rationale for the development of adiponectin-based interventions for the treatment of fibrotic diseases. The major antifibrotic actions of adiponectin across different organ systems are summarised in Figure 2.

Figure 2.

Summary of the conserved antifibrotic and anti-inflammatory actions of adiponectin across major fibrotic diseases. In the liver, adiponectin suppresses hepatic stellate cell activation through AMP-activated protein kinase (AMPK) signalling and inhibits Toll-like receptor 4 (TLR4)- and NF-κB-mediated inflammatory responses in Kupffer cells. In the lung, adiponectin inhibits epithelial-to-mesenchymal transition (EMT), reduces α-smooth muscle actin (α-SMA) expression and collagen deposition and suppresses TGF-β and NF-κB signalling. In the heart, adiponectin attenuates cardiac fibroblast activation, promotes macrophage autophagy via AMPK, suppresses NF-κB signalling and enhances anti-inflammatory cytokine production. In the kidney, adiponectin inhibits TGF-β signalling, reduces extracellular matrix synthesis and limits platelet-derived growth factor (PDGF)-induced mesangial cell proliferation through AMPK–mTOR signalling. In skeletal muscle, adiponectin suppresses inflammatory cytokine production and inhibits NF-κB signalling through activation of the AMPK–PGC-1α pathway. In the skin, adiponectin inhibits epithelial-to-mesenchymal transition, attenuates fibroblast activation, promotes dermal white adipose tissue expansion and suppresses focal adhesion kinase (FAK)-dependent profibrotic signalling. Collectively, these actions position adiponectin as a conserved endogenous regulator of fibrosis across diverse tissues. Created in BioRender.

Figure 2. Long description

A central illustration of a human body shows the lungs, heart, liver, kidneys, skeletal muscle, and a cross-section of skin. Six colored boxes point to these organs with specific biological actions.

* Hepatic (Yellow, top-left): Points to the liver. Lists decreased activation and decreased T G F-beta signalling in Hepatic Stellate cells via A M P K. Also lists decreased T L R-4 and N F-kappa B signalling in Kupffer cells.

* Pulmonary (Blue, top-right): Points to the lungs. Lists prevention of Epithelial to Mesenchymal transition in alveolar epithelial cells, decreased alpha-S M A and type-1 collagen deposition, and decreased T G F-beta and N F-kappa B in lung fibroblast.

* Cardiac (Green, middle-right): Points to the heart. Lists decreased Cardiac Fibroblast activation, increased Autophagy activation in macrophages via A M P K, inhibition of N F-kappa B signalling, and increased Anti-inflammatory cytokines (I L-10).

* Renal (Red, bottom-right): Points to the kidneys. Lists decreased T N F-alpha, T G F-beta and collagen, inhibition of synthesis of E C M components, and decreased P D G F-induced mesangial cell expansion via A M P K-m T O R.

* Dermal (Teal, bottom-left): Points to a skin cross-section. Lists inhibition of Epithelial to Mesenchymal transition, selective dermal white adipose tissue expansion, and decreased T G F-beta profibrotic effects via focal adhesion kinase signalling.

* Skeletal Muscle (Pink, middle-left): Points to the thigh muscle. Lists decreased inflammatory markers (T N F-alpha and I L-1 beta) and suppression of T G F-beta and N F-kappa B pathways via A M P K-P G C-1 alpha axis.

AdipoRON

AdipoRON is a synthetic small-molecule dual AdipoR1/AdipoR2 agonist identified through high-throughput screening of approximately 24,000 compounds against the intracellular ligand-binding cavity revealed by AdipoR crystal structural studies. Its discovery was validated in a study demonstrating improvements in glucose tolerance, insulin sensitivity and survival in genetically obese (db/db) mice fed a high-fat diet (Ref. Reference Okada-Iwabu, Yamauchi, Iwabu, Honma, Hamagami, Matsuda, Yamaguchi, Tanabe, Kimura-Someya, Shirouzu, Ogata, Tokuyama, Ueki, Nagano, Tanaka, Yokoyama and Kadowaki112). AdipoRON activates AMPK and PPARα signalling in skeletal muscle and liver, respectively, and has demonstrated antifibrotic activity across multiple experimental systems, establishing the therapeutic rationale for adiponectin receptor agonism as a promising treatment strategy (Ref. Reference Okada-Iwabu, Yamauchi, Iwabu, Honma, Hamagami, Matsuda, Yamaguchi, Tanabe, Kimura-Someya, Shirouzu, Ogata, Tokuyama, Ueki, Nagano, Tanaka, Yokoyama and Kadowaki112).

Evidence for the antifibrotic effects of AdipoRON has been reported in several organ systems. In cardiac fibrosis, treatment of aged (18-month-old) mdx mice, a model combining muscular dystrophy and ageing, reversed established cardiac fibrosis, reduced left ventricular hypertrophy and attenuated cardiac oxidative stress through activation of the AdipoR1/CaMKK2/AMPK signalling pathway (Ref. Reference Abou-Samra, Dubuisson, Marino, Selvais, Romain, Davis-López de Carrizosa, Noel, Beauloye, Brichard and Horman105). Similarly, chronic AdipoRON administration in aged wild-type mice improved skeletal muscle contractile force and mitochondrial oxidative phosphorylation capacity while reducing indices of age-related sarcopenic remodelling and fibrotic replacement through activation of AMPK/PGC-1α signalling (Ref. Reference Balasubramanian, Schaar, Gustafson, Smith, Howell, Greenman, Baum, Colman, Lamming, Diffee and Anderson106). In a murine model of systemic sclerosis-associated dermal fibrosis, oral AdipoRON reduced dermal thickness, collagen deposition, myofibroblast accumulation and microvascular abnormalities, with mechanistic studies demonstrating suppression of TGF-β1/Smad3 and FAK signalling (Ref. Reference Li, Song, Ruan, Xue and Zhao86). In hepatic fibrosis models, AdipoRON inhibited TGF-β/Smad signalling in activated HSCs, leading to reduced expression of collagen I and fibronectin and attenuation of profibrotic responses (Ref. Reference Sha, Gao, Deng, Wan, Zhuang, Hu and Wang113).

Despite its broad preclinical antifibrotic profile, the clinical advancement of AdipoRON has been hindered by several pharmacokinetic limitations, including modest aqueous solubility and relatively rapid in vivo clearance, which make sustained therapeutic concentrations difficult to achieve (Ref. Reference Onodera, Ghazvini Zadeh, Xu, Gordillo, Guo, Joffin, Yu, Scherer and Li114). To address these challenges, PEGylation-based formulation strategies have been developed, with PEGylated AdipoRON derivatives demonstrating improved plasma exposure and more durable metabolic benefits compared with the parent compound in animal models (Ref. Reference Onodera, Ghazvini Zadeh, Xu, Gordillo, Guo, Joffin, Yu, Scherer and Li114). Although no human clinical trials have been initiated to date, AdipoRON remains an important proof-of-concept compound for investigating adiponectin receptor signalling and continues to inform the development of next-generation adiponectin receptor agonists with improved drug-like properties.

ALY688

ALY688 (formerly ADP355) is a first-in-class, 10-amino acid peptidomimetic adiponectin receptor agonist derived from the receptor-binding globular domain of human adiponectin. Through the incorporation of D-amino acids and non-natural amino acid modifications, ALY688 was engineered to improve protease resistance and prolong biological activity relative to the native globular adiponectin sequence (Ref. Reference Dubuisson, Versele, Davis-López de Carrizosa, Selvais, Noel, Planchon, van den Bergh, Brichard and Abou-Samra93). ALY688 activates both AdipoR1 and AdipoR2, with preferential potency toward AdipoR1 and demonstrates low nanomolar activity in adiponectin receptor activation assays, exceeding that of native globular adiponectin in direct receptor signalling studies (Ref. Reference Dubuisson, Versele, Davis-López de Carrizosa, Selvais, Noel, Planchon, van den Bergh, Brichard and Abou-Samra93). To date, ALY688 has generated one of the most comprehensive preclinical datasets among adiponectin receptor agonists, demonstrating antifibrotic efficacy across multiple organ systems and disease models.

In skeletal muscle fibrosis, ALY688 treatment for 8 weeks in the mdx mouse model of DMD significantly improved grip strength, treadmill performance and maximal running velocity compared with vehicle-treated controls. These functional improvements were accompanied by marked reductions in collagen I deposition, α-SMA-positive myofibroblast accumulation and hydroxyproline content in both gastrocnemius and diaphragm muscle tissue. Mechanistic studies identified activation of the AMPK/PGC-1α axis and suppression of both NF-κB and TGF-β1 signalling as key mediators of these effects (Ref. Reference Dubuisson, Versele, Davis-López de Carrizosa, Selvais, Noel, Planchon, van den Bergh, Brichard and Abou-Samra93). Similar findings were observed in the more severe D2.mdx model, in which the sustained-release formulation ALY688-SR prevented diaphragm fibrosis and preserved diaphragm contractile function when administered during the early stages of disease progression (Ref. Reference Bellissimo, Gandhi, Castellani, Murugathasan, Delfinis, Thuhan, Garibotti, Seo, Rebalka, Hsu, Sweeney, Hawke, Abdul-Sater and Perry92).

The antifibrotic activity of ALY688 extends beyond skeletal muscle. In a murine model of NASH, ALY688 significantly reduced the expression of profibrotic genes, including Col1a1, Acta2 and TGFb1, while simultaneously improving hepatic steatosis (Ref. Reference Huang, Sung, Yan, He, Jin, Wang, Wu, Hsu, Pignalosa, Crawford, Sweeney and Xu115). Transcriptomic analyses revealed broad suppression of inflammatory and fibrotic gene programmes through AMPK-dependent signalling pathways. It demonstrated significantly less liver fibrosis after 12 weeks of treatment.

In a transverse aortic constriction model of heart failure with reduced ejection fraction, ALY688 attenuated left ventricular fibrosis and hypertrophy while preserving systolic function. Metabolomic analyses further demonstrated improvements in myocardial fatty acid oxidation and insulin sensitivity, suggesting restoration of cardiometabolic homeostasis in addition to direct antifibrotic effects (Ref. Reference Cho, Dadson, Sung, Ayansola, Mirzaesmaeili, Noskovicova, Zhao, Cheung, Radisic, Hinz, Sater, Hsu, Lopaschuk and Sweeney116).

In a murine model of systemic sclerosis, ALY688 significantly reduced dermal fibrosis, collagen deposition and myofibroblast accumulation, while also reversing established fibrosis when treatment was initiated after disease onset. Mechanistically, ALY688 inhibited TGF-β-induced fibroblast activation through activation of AMPK and suppression of Smad2/3 and FAK signalling, supporting its potential as a therapeutic strategy for systemic sclerosis (Ref. Reference Marangoni, Masui, Fang, Korman, Lord, Lee, Lakota, Wei, Scherer, Otvos, Yamauchi, Kubota, Kadowaki, Asano, Sato, Tourtellotte and Varga100). Collectively, the consistent antifibrotic activity of ALY688 across models of DMD, NASH, cardiac remodelling and systemic sclerosis, together with its enhanced stability, potent receptor activation and favourable pharmacokinetic profile, positions it as a promising adiponectin receptor agonists currently under development for the treatment of fibrotic diseases.