Irisin as a multi-target renoprotective mediator in chronic kidney disease: from molecular mechanisms to therapeutic perspectives

Chronic kidney disease (CKD) is a progressive, multifactorial disorder affecting approximately 9-13% of the global population and is driven by interrelated mechanisms including inflammation, oxidative stress, endothelial dysfunction, and fibrosis. Despite advances in therapies such as SGLT2 inhibitors, significant residual risk persists, necessitating the identification of novel multi-target therapeutic strategies.

This review aims to provide an integrated view of the molecular pathways involved in CKD progression and to critically study the emerging evidence for irisin - a myokine derived from proteolytic cleavage of fibronectin type III domain-containing protein 5 (FNDC5) - as a potential multi-target renoprotective mediator.

A narrative literature review was conducted using PubMed, Scopus, and Google Scholar. The search strategy incorporated combinations of Medical Subject Headings (MeSH) terms and keywords such as "irisin," "FNDC5," "molecular signalling" "mechanistic pathways" "chronic kidney disease," "renal fibrosis," "inflammation," "oxidative stress," "Nrf2," "NF-κB," "NLRP3 inflammasome," and "gut-kidney axis." Boolean operators (AND, OR) were used to refine the search. Relevant literature was selected based on the relevance of CKD pathophysiology and irisin biology.

Accumulating evidence demonstrates that irisin exerts pleiotropic protective effects in CKD by suppressing NF-κB and NLRP3 inflammasome activation, enhancing antioxidant defence via the Nrf2/HO-1 pathway, was associated with improvement in endothelial function in experimental models through AMPK/eNOS signalling, and attenuating TGF-β/Smad-mediated fibrosis. Additionally, irisin promotes autophagy and mitophagy, attenuates vascular smooth muscle cell pyroptosis, and modulates gut-kidney axis interactions by attenuating systemic inflammation and oxidative stress arising from elevated uremic toxins such as indoxyl sulfate and p-cresyl sulfate. Clinical observational studies suggest an inverse association between circulating irisin levels and CKD severity; however, these findings are confounded by various factors and do not establish causality.

Preclinical findings and human observational studies suggest possible therapeutic relevance of irisin to act as a biomarker and a therapeutic candidate in CKD. However, the translational application of irisin in CKD remains speculative due to various confounders such as incomplete receptor characterisation, peptide instability, dosing uncertainty, assay heterogeneity, exercise status, variation in muscle mass, and dialysis status.