Sialyltransferase7A promotes cardiomyocyte ferroptosis induced by sorafenibthrough increase in HIF-1ɑ expression

Abstract

Abstract Sorafenib is a widely used in the treatment of many different types of cancer. Studies indicate that sorafenib has been associated with several cardiotoxicities including cardiac enzyme elevations, contractile dysfunction, and heart failure. Clinical observation shows that cardiotoxicity due to sorafenib treatment is largely underestimated, but the mechanism of cardiovascular toxicity is unclear. In this study, we first reported that one of the sialyltransferase family member sialyltransferase7A (Siat7A), promotes sorafenib induced cardiomyocyte ferroptosis by stimulating hypoxia-inducible factor 1α (HIF-1ɑ) expression. Siat7A increased in cardiotoxicity of rats subjected to sorafenib infusion, myocardial hypertrophy marker ANP and α-actinin increased, while the expression of glutathione peroxidase 4 (GPX4) and SLC7A11, the markers of ferroptosis decreased. These results suggested that myocardial hypertrophy aggravated and ferroptosis increased in vivo. Siat7A overexpression significantly upregulated the level of Siat7A and cardiomyocytes ferroptosis, while Siat7A knockdown inhibited Siat7A and cardiomyocytes ferroptosis stimulated by sorafenib in vitro. HIF-1ɑ expression was stimulated by sorafenib both in vitro and in vivo. Mechanistically, we further revealed that sorafenib induced the activation of HIF-1ɑ in parallel to Siat7A in cardiomyocyte ferroptosis, that is HIF-1ɑ activation was inhibited in Siat7A knockdown cardiomyocytes and activated after Siat7Aoverexpression. Based on these findings, we conclude that Siat7A promotes cardiomyocyte ferroptosis induced by sorafenib through increase in HIF-1ɑ expression.