SGLT2 inhibitors attenuate diabetic kidney disease by suppressing YAP dependent ferroptosis

Sodium-glucose cotransporter 2 (SGLT2) inhibitors provide renal protection in diabetic kidney disease (DKD) through mechanisms beyond glucose lowering, but these remain incompletely understood. Here we show that Yes-associated protein 1 (YAP)-dependent ferroptosis contributes to renal tubular injury in DKD and that suppression of this pathway underlies part of the renoprotective effects of dapagliflozin. In human DKD kidney tissues, nuclear YAP accumulation correlates positively with ferroptosis markers acyl-CoA synthetase long-chain family member 4 (ACSL4) and 4-hydroxynonenal, and negatively with renal function. In a diabetic rat model, dapagliflozin attenuates renal dysfunction, tubular injury, and fibrosis alongside reduced YAP activation and ferroptosis. In high-glucose-treated renal tubular epithelial cells, YAP promotes nuclear translocation, upregulates ACSL4 and transferrin receptor expression, induces iron accumulation and mitochondrial damage, and drives ferroptotic cell death. YAP knockdown and pharmacological inhibition both confirm an upstream regulatory role for YAP in ferroptosis. Mechanistically, YAP and TEAD4 enhance ACSL4 promoter activity through a conserved TEAD-binding motif, an effect suppressed by dapagliflozin. These findings identify the YAP/TEAD4-ACSL4 axis as a therapeutic target underlying glucose-independent renoprotection by SGLT2 inhibition.