Abstract / Summary
Cardiac fibrosis is a major pathological feature of several cardiovascular diseases and is characterized by excessive extracellular matrix deposition, leading to ventricular stiffening, impaired cardiac function, and ultimately heart failure. Despite its substantial clinical burden, therapies specifically targeting the fibrotic process remain limited. Irisin, a myokine generated by cleavage of fibronectin type III domain-containing protein 5 (FNDC5), has emerged as a cardioprotective factor with potential antifibrotic properties. This review critically examines current evidence on the molecular mechanisms underlying the cardioprotective and antifibrotic effects of irisin, with particular emphasis on integrin αVβ5, AMP-activated protein kinase (AMPK), and their associated signaling pathways. Preclinical studies indicate that irisin engages context-dependent signaling mechanisms that vary according to cell type and pathological setting. These include integrin αVβ5-dependent activation of AMPK or AKT, modulation of oxidative and nitrosative stress, inhibition of ferroptosis through SIRT1/p53 signaling, attenuation of NLRP3 inflammasome activation, preservation of mitochondrial homeostasis, activation of Nrf2-dependent antioxidant responses, and suppression of TGF-β1/Smad2/3-mediated fibroblast activation. Across experimental models, these molecular effects are associated with reduced fibroblast activation and extracellular matrix accumulation, improved mitochondrial and redox homeostasis, and attenuation of pathological cardiac remodeling. Collectively, current evidence identifies irisin as a multifaceted regulator of pathological cardiac remodeling with potential relevance to the attenuation of cardiac fibrosis. However, the available evidence remains predominantly preclinical, and substantial uncertainties regarding receptor and pathway specificity, pharmacokinetics, optimal delivery, safety, and therapeutic efficacy must be resolved before clinical translation.