SOX4 Promotes Ferroptosis to Aggravate Myocardial Ischemia/Reperfusion Injury Through Elevating DAPK1 Expression.

Ferroptosis is considered to be a pathological mechanism of myocardial ischemia-reperfusion injury (MI/RI). Previous studies have shown that death-associated protein kinase 1 (DAPK1) was involved in MI/RI development, but the underlying mechanism remains unclear. Mice with ligation of the left anterior descending artery followed by reperfusion, and HL-1 cells subjected to hypoxia/reoxygenation (H/R) induction were used as MI/RI animal and cell models, respectively. The pathological status of the mouse heart was evaluated by TTC staining, HE staining and echocardiography. Cell viability was examined using CCK-8. DAPK1, SRY-box transcription factor 4 (SOX4) and ferroptosis-related indicators were determined using RT-qPCR, western blot, commercial kits and DCFH-DA method. The interaction between SOX4 and DAPK1 promoter was validated using dual luciferase assay and ChIP assay. In MI/RI mice and H/R-induced cardiomyocytes, DAPK1 and SOX4 expression was abnormally elevated compared with that in control groups. In addition, silencing of DAPK1 or SOX4 improved cardiomyocyte injury and attenuated ferroptosis in H/R-induced cardiomyocytes. At the molecular levels, SOX4 could promote DAPK1 transcription and elevate DAPK1 expression via interacting with the DAPK1 promoter. Furthermore, SOX4 knockdown alleviated cardiomyocyte injury and mitigated ferroptosis through inhibiting DAPK1 expression, thereby relieving MI/RI in mice. Our results reveled that SOX4 promoted cardiomyocyte injury and exacerbated ferroptosis, thereby intensifying MI/RI through increasing DAPK1 expression.