Dapagliflozin ameliorates diabetic kidney disease by inhibiting oxidative stress and AIM2-dependent pyroptosis via SIRT1 activation.

Diabetic kidney disease (DKD), a predominant microvascular complication of diabetes mellitus, still lacks curative therapies to completely halt its progressive deterioration. Our study investigated the renoprotective mechanisms of dapagliflozin (dapa) in DKD. Through bioinformatic analysis of clinical DKD datasets, preclinical in vivo and in vitro assays, we identified absent in melanoma 2 (AIM2) as a critical pyroptosis-associated gene upregulated in DKD. In silico structure-based validation revealed that dapa stably binds to the catalytic domain of silent information regulator 1 (SIRT1) via key residues GLN-361 and SER-365, suggesting its potential to modulate SIRT1 deacetylase function. Gain- and loss-of-function assays confirmed that SIRT1 is the core functional target of dapa: dapa upregulated SIRT1 protein expression to inhibit nuclear factor-κB (NF-κB) signaling, thereby blocking AIM2 inflammasome-mediated renal tubular pyroptosis and oxidative damage. These findings reveal a previously unreported mechanism by which dapa regulates SIRT1/NF-κB/AIM2 signaling to exert renoprotection, and provide promising therapeutic targets for the clinical management of DKD.