Irisin suppresses inflammation, oxidative stress, and fibrosis in CKD via multi-target renoprotective mechanisms.

Chronic kidney disease (CKD) is a progressive, multifactorial disorder affecting approximately 9-13% of the global population, driven by interrelated mechanisms including inflammation, oxidative stress, endothelial dysfunction, and fibrosis. Despite advances with therapies like SGLT2 inhibitors, significant residual risk persists, necessitating novel multi-target strategies. Irisin, a myokine derived from FNDC5, is emerging as a potential pleiotropic mediator to address these complex pathways.

This study conducted a narrative literature review to synthesize evidence on irisin's role in CKD progression. Researchers systematically searched PubMed, Scopus, and Google Scholar using 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) refined the search, and relevant literature was selected based on its pertinence to CKD pathophysiology and irisin biology.

Accumulating evidence demonstrates that irisin exerts pleiotropic protective effects in CKD by modulating several key molecular pathways. It suppresses NF-κB and NLRP3 inflammasome activation, which are central to inflammatory processes. Irisin also enhances antioxidant defense via the Nrf2/HO-1 pathway, crucial for mitigating oxidative stress. Experimental models showed irisin was associated with improved endothelial function through AMPK/eNOS signalling, and it attenuated TGF-β/Smad-mediated fibrosis, a hallmark of CKD progression. Furthermore, irisin promotes autophagy and mitophagy, cellular processes vital for clearing damaged components. It also attenuates vascular smooth muscle cell pyroptosis and modulates gut-kidney axis interactions by reducing systemic inflammation and oxidative stress caused by uremic toxins like indoxyl sulfate and p-cresyl sulfate. These findings collectively highlight irisin's broad therapeutic potential.

Irisin demonstrates pleiotropic renoprotective effects in CKD by suppressing NF-κB and NLRP3 inflammasome activation, enhancing antioxidant defense via Nrf2/HO-1, and attenuating TGF-β/Smad-mediated fibrosis.