Canagliflozin Alleviates Pressure Overload-Induced Cardiac Dysfunction via PINK1 Regulation by Inhibiting Mitophagy-Driven Ferroptosis

Background: Targeting cardiac remodelling process represents a crucial strategy for early intervention in management of heart failure (HF). Landmark clinical trials such as the Canagliflozin Cardiovascular Assessment Study (CANVAS) program have demonstrated that canagliflozin reduces the risk of cardiovascular events in patients with type 2 diabetes and high cardiovascular risk, although its precise mechanisms require further elucidation. We recently showed that canagliflozin inhibits excessive Mitophagy and alleviates cardiac remodelling in the mouse model. Given that excessive Mitophagy may participate in Ferroptosis in the failing heart, elucidating this crosstalk is essential to understand whether canagliflozin confers extra protection.

Methods: In an isoproterenol-induced HF mouse model, we assessed Mitophagy, Ferroptosis, and cardiomyocyte death. Ferroptosis inhibitor, Mitophagy inducers and inhibitors, and modulation of PTEN-induced putative kinase 1 (PINK1) were used to dissect the mitophagy-ferroptosis relationship.

Results: In a mouse model of HF, isoproterenol induces stress-evoked cardiac dysfunction, and elevated cardiac Mitophagy coincides with this. Further investigation revealed that initial compensatory Mitophagy ultimately failed to maintain metabolic homeostasis, concomitant with autophagic cell death and Ferroptosis. Treatment with canagliflozin effectively attenuated cardiomyocyte death. Notably, canagliflozin decreased p-AMPK levels in heart tissue. Mechanistically, canagliflozin suppressed excessive Mitophagy and restored the protein levels of GPX4. PINK1 overexpression partially reversed the cardioprotective effects of canagliflozin. Furthermore, canagliflozin demonstrated direct antiferroptosis efficacy in an imidazole ketone erastin (IKE)-induced model.

Conclusions: Canagliflozin attenuates stress-induced cardiomyocyte Ferroptosis in the late phase by inhibiting PINK1-mediated excessive Mitophagy and restoring GPX4 expression, thus revealing the modulation of the mitophagy-ferroptosis axis as a novel cardioprotective mechanism in HF.