Myocardial infarction-induced heart failure (MI-HF) remains a major contributor to cardiovascular mortality, yet the molecular mechanisms underlying its progression, particularly those involving ferroptosis, are not fully understood. This study aimed to investigate the role of SREBF2 in regulating ferroptosis and mitochondrial homeostasis in MI-HF. Differentially expressed genes were screened from the GSE24519 dataset and overlapped with ferroptosis-related genes, identifying SREBF2 as a potential target. SREBF2 expression was examined in human HF samples, MI-HF mice, and oxygen-glucose deprivation (OGD)-injured cardiomyocytes. Functional roles of SREBF2 were evaluated through in vivo overexpression in mice and in vitro assays in cardiomyocytes. Ferroptosis markers (GPX4, ACSL4, ROS, MDA, Fe²⁺, GSH), mitochondrial membrane potential (ΔΨm), and mitophagy-related proteins (PINK1, Parkin, p62) were assessed. Chromatin immunoprecipitation and rescue experiments were conducted to confirm the transcriptional regulation of Caveolin-1 (Cav-1) by SREBF2. SREBF2 was significantly downregulated in MI-HF tissues and OGD-injured cardiomyocytes. Overexpression of SREBF2 improved cardiac function, reduced infarct size and fibrosis, and enhanced myocardial remodeling in MI-HF mice. SREBF2 suppressed ferroptosis by reducing ROS, Fe²⁺, and MDA levels, restoring GSH and GPX4, and downregulating ACSL4. Mitochondrial dysfunction was alleviated via improved ΔΨm, reduced mitoROS, and balanced mitochondrial dynamics. SREBF2 activated PINK1/Parkin-mediated mitophagy, which was essential for its anti-ferroptotic effects. Mechanistically, SREBF2 directly bound to and transcriptionally activated Cav-1, which mediated downstream mitophagy activation and ferroptosis inhibition. Cav-1 knockdown or mitophagy inhibition abrogated SREBF2-induced mitochondrial protection and cytoprotection. The results of our study demonstrate that SREBF2 mitigates MI-induced HF by activating the Cav-1/PINK1/Parkin axis to promote mitophagy and inhibit ferroptosis. These findings reveal a novel cardioprotective mechanism and identify SREBF2 as a promising therapeutic target in heart failure.
