Protective mitophagy in human hypoxic cardiomyocytes: mechanistic insights into SGLT2 inhibitor Dapagliflozin cardioprotection in ischemic injury

Background Acute myocardial infarction (AMI) remains a leading cause of mortality worldwide, with cardiomyocyte death under hypoxic stress being a critical pathogenic mechanism. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrate cardiovascular benefits beyond glycemic control, yet their protective mechanisms in ischemic injury remain incompletely understood. Methods This study investigated dapagliflozin’s effects on human cardiomyocytes derived from induced pluripotent stem cell (iPSC-CMs) subjected to hypoxic stress. iPSC-CMs were applied to hypoxia with or without dapagliflozin treatment, followed by RNA-sequencing, qPCR validation, Western blotting, immunofluorescence, flow cytometry, and autophagy flux assays. Seahorse energy analyzer was used for cardiomyocyte metabolism analysis. Results RNA-sequencing revealed that dapagliflozin reversed hypoxia-induced transcriptomic alterations, particularly in 66 genes associated with mitochondrial dysfunction. Dapagliflozin activated the AMPK/SIRT1/SIRT3 signaling axis, upregulated autophagy/mitophagy markers (LC3B, BECN1, Parkin). Seahorse cardiomyocyte metabolism analysis results demonstrated that dapagliflozin improved iCM mitochondrial function by restoring mitochondrial membrane potential, mitophagy capability and reduced hypoxia-related apoptosis. Autophagy inhibition with bafilomycin A1 abolished cardioprotection, confirming autophagy-dependent mechanisms. Conclusions These findings suggest that dapagliflozin protects cardiomyocytes through enhanced SIRT1/3-associated mitochondrial quality control and adaptive autophagy, providing mechanistic evidence supporting SGLT2 inhibitors' therapeutic potential in mitigating myocardial ischemic injury.