AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Sodium-Glucose Cotransporter 2 Inhibitors Restore Myocardial Energy Metabolism to Mitigate Doxorubicin Cardiotoxicity in Adult Zebrafish
By Liu L, Hsiao HH, Liu YC et al.
Background: Doxorubicin (DOX) is a widely used chemotherapeutic agent whose dose-dependent cardiotoxicity limits its clinical use. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are cardioprotective in heart failure, but their effects and mechanisms against DOX-induced cardiotoxicity remain unclear. Hypothesis: We hypothesized that the SGLT2i empagliflozin and canagliflozin protect against DOX cardiotoxicity by preserving cardiac function and myocardial energy metabolism while limiting early ferroptotic stress. Methods: Adult AB zebrafish received intraperitoneal DOX (20 mg/kg every 17 days) over six weeks, with or without daily retro-orbital empagliflozin (6.2 mg/kg) or canagliflozin (24.7 mg/kg). Survival, ventricular histology, electrocardiography, echocardiography, myocardial ATP, AMPK/SIRT1/PGC-1α signaling, and ferroptosis-related markers were assessed at 7-42 days post-injection (dpi). Groups were compared by one-way ANOVA (mean ± SD). Results: DOX reduced survival to 88%, 65%, and 45% at 14, 28, and 42 dpi, versus 97-88% in vehicle controls; co-treatment improved survival to 97/90/80% (empagliflozin) and 91/88/70% (canagliflozin). DOX progressively lowered ventricular trabecular density and prolonged PR interval, QRS duration, and corrected QT, reaching significance by 28 dpi (p<0.05), while both inhibitors significantly preserved structure and conduction. Echocardiography showed DOX raised the E/A ratio and myocardial performance index at 28-42 dpi, which both agents attenuated (p<0.05). DOX produced a late decline in myocardial ATP at 28-42 dpi that both inhibitors prevented, maintaining near-control levels (p<0.05). Empagliflozin significantly restored phosphorylated AMPK, SIRT1, and PGC-1α at 14-28 dpi (p<0.05), whereas canagliflozin showed a smaller, non-significant effect. In a complementary analysis, DOX induced early lipid-peroxidation stress, with increased Acsl4 and compensatory Gpx4 and Slc7a11 upregulation, consistent with a ferroptosis-prone state rather than overt ferroptosis; SGLT2i blunted the Acsl4 rise at 7 dpi. Conclusions: Empagliflozin and canagliflozin reduced DOX-induced mortality and preserved cardiac structure, conduction, and function in adult zebrafish. Protection tracked with maintained myocardial ATP, reactivation of AMPK/SIRT1/PGC-1α signaling, and attenuation of early ferroptotic stress, with empagliflozin showing stronger early effects. These findings support SGLT2 inhibition as a multi-pathway cardioprotective strategy in cardio-oncology and validate adult zebrafish as a translational platform.