Abstract
Hypertension serves as a major contributing factor to various cardiovascular disorders, including heart failure. Ferroptosis-induced cardiomyocyte loss is recognized as a novel contributor to myocardial remodeling in heart failure. Membrane-associated RING-CH-type finger 6 (Marchf6) is a newly identified gene that regulates ferroptosis and is implicated in various disease processes. However, the role of Marchf6 in modulating cardiomyocyte ferroptosis and its impact on hypertension-induced myocardial remodeling remain unexplored. This study aimed to investigate whether Marchf6 influences myocardial remodeling through the regulation of ferroptosis and to explore the underlying molecular mechanisms. Our findings indicated that there was a decrease in Marchf6 levels in both animal and cellular models established through Angiotensin II (Ang II) stimulation. Overexpression of Marchf6 conferred resistance to Erastin-induced ferroptosis, while Marchf6 knockdown increased sensitivity to ferroptosis. In the Ang II cellular model, Marchf6 overexpression enhanced cell viability, inhibited cardiomyocyte hypertrophy, and reversed ferroptosis-related indicators, whereas Marchf6 knockdown exhibited opposite effects. Animal model studies indicated that Marchf6 overexpression significantly improved cardiac function, alleviated myocardial hypertrophy and fibrosis, and suppressed ferroptotic death levels. Mechanistic investigations revealed that Marchf6 significantly regulated the stability of ACSL4 protein, with Marchf6 overexpression accelerating ACSL4 protein degradation. In cardiomyocytes overexpressing Marchf6, ACSL4 overexpression notably reversed the regulatory impact of Marchf6 on cardiac cell hypertrophy and ferroptosis triggered by Ang II. Collectively, our findings suggest that Marchf6 may mitigate cardiomyocyte ferroptosis by promoting ACSL4 degradation, thereby alleviating hypertension-induced myocardial remodeling. This study not only uncovers a novel regulatory mechanism of cardiomyocyte ferroptosis in myocardial remodeling but also presents a viable target for the management of hypertension-related cardiac diseases.