Upstream Stimulatory Factor 2 Protects Cardiomyocytes by Regulating Mitochondrial Homeostasis

Myocardial ischemia and hypoxia are the main causes of heart failure, and cardiomyocyte apoptosis induced by mitochondrial injury is the basis of adverse heart remodeling and heart failure. Upstream stimulatory factor 2 (USF2), a transcription factor involved in multiple cellular processes, was recently shown to play an active role in mitochondrial function and energy homeostasis. However, its involvement in cardiovascular disease has not been previously reported. In this study, we demonstrated that under hypoxic conditions, USF2 protein expression can be degraded via the ubiquitin-proteasome pathway in cardiomyocytes. The deletion of USF2 results in mitochondrial dysfunction and exacerbates mitochondrial damage, ultimately promoting apoptosis. Mechanistically, we demonstrated that USF2 deficiency induces apoptosis in cells by modulating the AMPK/mTOR signaling pathway. In conclusion, this study provides new insights into the protective role of USF2 in hypoxic cardiomyocyte injury and indicates that USF2 could be a potential therapeutic target for myocardial hypoxia.