Dapagliflozin Protects Cardiomyocytes against Doxorubicin-Induced Toxicity by Modulating Sirtuin 1/Sirtuin 3 and Ferroptosis Pathway.

Cardiac dysfunction can be aggravated by chemotherapeutic agents, including doxorubicin, through mechanisms involving mitochondrial dysfunction, elevated oxidative stress, suppression of sirtuin (SIRT1/SIRT3) signaling, and activation of apoptotic and ferroptotic pathways. Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been demonstrated to possess cardioprotective effects; however, the interplay between sirtuin signaling and ferroptosis in dapagliflozin-mediated cardioprotection under doxorubicin-induced stress remains unclear. In the present study, dapagliflozin restored cellular function in H9c2 cardiomyoblasts exposed to doxorubicin by reducing apoptosis, oxidative stress, and lipid peroxidation, while preserving mitochondrial respiration and glycolytic function. Dapagliflozin reversed doxorubicin-induced downregulation of SIRT1, SIRT3, GPX4, BCL2, OPA1, and PGC1α, and mitigated the upregulation of ACSL4, BAX, and DNM1 at both transcriptional and translational levels. The cardioprotective efficacy of dapagliflozin under cellular stress depends critically on SIRT1/SIRT3 signaling and ferroptosis regulation, as pharmacological inhibition of these sirtuins abolished its protective potentials; conversely, these effects were enhanced by ferroptosis suppression and attenuated by its induction. Furthermore, dapagliflozin-mediated inhibition of ferroptosis downregulated SIRT1/SIRT3 expression, suggesting a potential feedback mechanism under chemotherapeutic stress. Notably, sirtuin inhibition compromised these protective responses despite ferroptosis blockade, highlighting SIRT1/SIRT3 as upstream regulators of dapagliflozin-mediated cardioprotection and underscoring the necessity of sirtuin activity for ferroptosis suppression. Collectively, these findings reveal that dapagliflozin mitigates doxorubicin-induced cardiotoxicity via the coordinated regulation of SIRT1/SIRT3 signaling and ferroptosis pathways, involving key mediators of apoptosis, mitochondrial dynamics, and lipid metabolism.