Adiponectin Therapeutics for Fibrotic Diseases: Current Knowledge and Future Perspectives
Divya Shah, Jialing Tang, Eddie Tam, Henry H Hsu, Gary SweeneyAbstract
Background
Fibrosis is characterised by the pathological accumulation of extracellular matrix components and represents both a driver and consequence of chronic tissue injury across multiple organs and is a major contributor to global morbidity and mortality. Despite this substantial clinical burden, approved antifibrotic therapies remain limited. Adiponectin, an adipokine secreted predominantly by adipocytes, is an endogenous antifibrotic mediator with potential therapeutic applications.
Methods
This review examines the pathobiology of fibrosis, the molecular mechanisms underlying adiponectin-mediated antifibrotic effects, and current advances in adiponectin-based therapeutic development. Evidence from preclinical studies across multiple organ system is discussed, with a focus on adiponectin signaling pathways and receptor agonists.
Results
Adiponectin actsprimarily through its cognate receptors AdipoR1 and AdipoR2, adiponectin suppresses key profibrotic signalling cascades, including TGF-β/Smad, NF-κB, Wnt/β-catenin, Notch and platelet-derived growth factor pathways, while simultaneously promoting anti-inflammatory, antioxidant and cytoprotective responses. Preclinical studies demonstrate that adiponectin deficiency exacerbates fibrotic remodelling in the liver, lungs, heart, kidneys, skeletal muscle and skin, whereas genetic or pharmacological augmentation of adiponectin signalling attenuates fibrosis progression. Two adiponectin receptor agonists, the small molecule AdipoRON and the peptide mimetic ALY688, have shown promising antifibrotic efficacy across multiple disease models.
Conclusions
Adiponectin signaling represents a promising therapeutic strategy for the prevention and treatment across multiple organs. Further investigation is needed to address current challenges and establish the safety, efficacy, and translational potential of adiponectin-based therapies in clinical settings.