Dapagliflozin promotes metabolic reprogramming against myocardial infarction through the MAPK-FOXO3-STC1 and HIF-1a-STC1 pathways

Abstract

Background

Myocardial infarction (MI) results in mitochondrial dysfunction and metabolic imbalance, ultimately causing cellular injury and impaired cardiac function. Dapagliflozin (DAPA) has been shown to reduce cardiovascular mortality; however, the underlying mechanisms by which it confers cardioprotection in MI remain incompletely understood.

Methods

To explore the protective role of DAPA, an oxygen-glucose deprivation (OGD) model was established in H9c2 cardiomyoblasts to assess its effects on cell proliferation, apoptosis, metabolism, and mitochondrial function. A series of molecular assays, including qRT-PCR, Western blotting, chromatin immunoprecipitation (ChIP), dual-luciferase reporter analysis, and rescue experiments, were performed to elucidate the involvement of HIF-1α, FOXO3, and STC1 in DAPA-mediated responses. In vivo, the cardioprotective effects of DAPA were validated using a rat model of MI.

Results

DAPA promoted proliferation, inhibited apoptosis, and restored glucose uptake, ATP generation, and mitochondrial activity in OGD-treated H9c2 cells by modulating the JNK signaling pathway, promoting FOXO3 degradation, and engaging the HIF-1α–STC1 axis. In MI rats, DAPA significantly reduced infarct size, improved cardiac function, and alleviated myocardial fibrosis and apoptosis. Rescue experiments further confirmed that overexpression of STC1 potentiated DAPA's effects, whereas STC1 knockdown attenuated them.

Conclusion

These findings indicate that the HIF-1α–FOXO3–STC1 pathway plays a central role in the cardioprotective mechanisms of DAPA. By modulating the MAPK–FOXO3–STC1 and HIF-1α–STC1 signaling cascades, DAPA improves mitochondrial function and metabolic homeostasis, supporting its therapeutic potential in the treatment of MI.