Canagliflozin reverses doxorubicin-induced cardiotoxicity via restoration of autophagic homeostasis.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been reported as successful for preventing doxorubicin (DOX) -induced cardiotoxicity (DIC), but the underlying mechanisms are elusive. This study aimed to determine whether canagliflozin, an SGLT2i, protects against DIC by regulation of autophagic flux in cardiomyocytes through a mechanism independent of SGLT2. The differentially expressed autophagy-related genes (ARGs) in DIC were analyzed. Neonatal rat cardiomyocytes (NRCMs), H9C2 rat cardiomyocytes or C57BL/6 mice were treated with canagliflozin or vehicle. The effects on cellular apoptosis and autophagy were investigated using qRT-PCR, western blotting and immunofluorescence. Additionally, cardiac function, myocardial fibrosis, and apoptosis of cardiomyocytes were also assessed in mice. The potential molecular targets of canagliflozin were identified through molecular docking analysis. A total of 26 differentially expressed ARGs were identified. Canagliflozin significantly activated autophagic flux and inhibited apoptosis of cardiomyocytes in both DOX-treated H9C2 rat cardiomyocytes and NRCMs. In a murine model of DIC, canagliflozin improved cardiac dysfunction by suppressing cardiac remodeling, fibrosis, and apoptosis. Moreover, canagliflozin promoted autophagy by enhancing SIRT1 levels and inhibiting the PI3K/Akt/mTOR signaling pathway. Immunofluorescence assays revealed that canagliflozin promoted the translocation of LC3 from the nucleus to the cytoplasm. Molecular docking analysis confirmed that canagliflozin has high affinity for targets associated with DIC. These findings suggest that canagliflozin protects cardiomyocytes from DOX-induced cell death by activating SIRT1, inhibiting the PI3K/Akt/mTOR pathway, and enhancing autophagic flux.