Novel applications of SIRT1 in Chronic Kidney Disease.

Chronic kidney disease (CKD) has become a global public health issue, with progressive kidney fibrosis serving as a key pathological process leading to kidney failure, and current therapeutic approaches remain largely ineffective in reversing this progression. SIRT1, as an NAD⁺-dependent deacetylase, plays a central protective role in counteracting kidney fibrosis, inflammation, oxidative stress, and autophagic dysfunction by regulating multiple signaling pathways, and has emerged as a promising target in CKD treatment. This review systematically elaborates on the mechanisms regulating SIRT1 expression and activity in CKD, its protective roles in core pathological processes, and summarizes recent advances in targeting SIRT1 for CKD therapy. Functionally, SIRT1 antagonizes kidney fibrosis by deacetylating Smad3/Smad4 and inhibiting epithelial-mesenchymal transition; curbs inflammatory cascades through dual blockade of NF-κB transcriptional activity and NLRP3 inflammasome assembly; constructs a multi-layered antioxidant defense network by activating the Nrf2/ARE pathway, regulating FOXO transcription factors, and enhancing mitochondrial biogenesis; and restores autophagic flux to clear damaged organelles. Regarding complications, SIRT1 inhibits vascular calcification and improves kidney anemia by stabilizing HIF-1α to promote EPO synthesis and inhibiting ferroptosis. In terms of therapeutic strategies, the synthetic SIRT1 agonist SRT2104 has completed Phase I-II clinical trials with favorable safety profiles, but its pharmacokinetic limitations and the disconnect from preclinical effects pose barriers to clinical translation; NAD⁺ precursor strategies offer theoretical advantages but lack clinical evidence in CKD populations. In summary, SIRT1 integrates metabolic sensing, transcriptional regulation, and post-translational modification functions, serving as a key molecular hub linking upstream pathological signals to downstream organ damage in CKD. Precise modulation of SIRT1 activity may offer a novel multi-target synergistic therapeutic strategy for CKD.