A review of the sirtuins family: pivotal regulators and emerging therapeutic targets in renal fibrosis.

Renal fibrosis represents the common pathological endpoint of chronic kidney disease (CKD) progression, yet effective therapies remain limited. The sirtuins family (SIRT1-SIRT7), NAD+-dependent deacetylases, functions as a critical molecular hub linking metabolism, stress responses, and homeostasis. This review systematically delineates the integrated anti-fibrotic mechanisms of sirtuins: SIRT1, SIRT3, and SIRT6 suppress TGF-β/Smad and Wnt/β-catenin signaling; activate the AMPK/PGC-1α axis to correct metabolic dysregulation; promote autophagy via FoxO and TFEB; and alleviate oxidative stress and inflammation through Nrf2 and NF-κB modulation. We further summarize diverse therapeutic strategies targeting sirtuins-including natural compounds, traditional Chinese medicine formulations, synthetic drugs, gene therapy, bioactive peptides, and exercise training-that exhibit significant anti-fibrotic efficacy in preclinical models. Despite promising evidence, clinical translation faces challenges including cell-type-specific functional duality, disease-stage-dependent effects, and the need for highly selective modulators with improved bioavailability and renal targeting. This review highlights sirtuins as a multi-dimensional regulatory network and a promising therapeutic frontier in renal fibrosis, while outlining key obstacles and future directions for clinical application.