The Journal of Pharmacy and Pharmacology · Oct 1, 2026
Dapagliflozin attenuates cardiomyocyte hypertrophy by inhibiting KEAP1-NRF2-mediated ferroptosis pathway
By Liang L, Wang Q, Zhen H et al.
OBJECTIVES: Myocardial hypertrophy is a common pathological process in various cardiovascular diseases and may ultimately lead to heart failure. As a sodium-glucose cotransporter 2 inhibitor, dapagliflozin (DAPA) has been demonstrated to be cardioprotective, in addition to its hypoglycemic effect. However, the precise mechanism of DAPA in myocardial hypertrophy remains unclear. METHODS: H9C2 rat cardiomyoblast cell line were subjected to isoproterenol (ISO)-induced hypertrophy and erastin-induced ferroptosis, and treated with DAPA, ferrostatin-1, KEAP1 activator K67, or inhibitor ML334. Hypertrophic markers and cell surface area were assessed by quantitative real-time polymerase chain reaction and rhodamine-phalloidin staining. Ferroptosis was evaluated by measuring glutathione (GSH), malondialdehyde, reactive oxygen species, lipid peroxidation, intracellular ferrous iron, and mitochondrial membrane potential. Protein expression of KEAP1, NRF2, solute carrier family 7 member 11, and GSH peroxidase 4 was determined by western blot. KEY FINDINGS: DAPA attenuated ISO-induced cardiomyocyte hypertrophy and suppressed ferroptosis by inhibiting KEAP1 to activate NRF2, upregulating downstream targets. GSH peroxidase 4 knockdown abolished DAPA's protective effects. KEAP1 reactivation with K67 reversed DAPA-mediated cardioprotection, whereas KEAP1 inhibition with ML334 recapitulated it. CONCLUSIONS: DAPA exerts a protective role in myocardial hypertrophy by inhibiting KEAP1-NRF2-mediated ferroptosis pathway, providing novel insights into the potential mechanism and application of DAPA on cardiovascular diseases.