SREBF2 mitigates MI-induced heart failure by activating the Cav-1/PINK1/Parkin axis to promote mitophagy and inhibit ferroptosis, identifying SREBF2 as a promising therapeutic target.
Key Findings
Results
SREBF2 was significantly downregulated in MI-HF tissues and OGD-injured cardiomyocytes.
Differentially expressed genes were screened from the GSE24519 dataset and overlapped with ferroptosis-related genes to identify SREBF2 as a potential target.
SREBF2 downregulation was confirmed in human heart failure samples, MI-HF mice, and oxygen-glucose deprivation (OGD)-injured cardiomyocytes.
The convergence of differential expression analysis and ferroptosis gene databases positioned SREBF2 as a candidate regulator of ferroptosis in ischemic heart failure.
Results
Overexpression of SREBF2 improved cardiac function, reduced infarct size and fibrosis, and enhanced myocardial remodeling in MI-HF mice.
In vivo SREBF2 overexpression was achieved via viral or plasmid delivery in MI-HF mouse models.
Functional improvements were assessed by standard cardiac metrics including infarct size quantification and fibrosis markers.
Myocardial remodeling parameters were also improved following SREBF2 overexpression.
Results
SREBF2 suppressed ferroptosis by modulating key ferroptosis markers including ROS, Fe²⁺, MDA, GSH, GPX4, and ACSL4.
SREBF2 activated PINK1/Parkin-mediated mitophagy, which was essential for its anti-ferroptotic effects.
Mitophagy-related proteins PINK1, Parkin, and p62 were assessed to confirm mitophagy activation.
Inhibition of mitophagy abrogated the anti-ferroptotic effects of SREBF2, demonstrating that mitophagy activation is mechanistically required.
The PINK1/Parkin pathway is a canonical mitophagy signaling cascade, and its activation by SREBF2 links mitochondrial quality control to ferroptosis suppression.
Results
SREBF2 directly bound to and transcriptionally activated Caveolin-1 (Cav-1), which mediated downstream mitophagy activation and ferroptosis inhibition.
Chromatin immunoprecipitation (ChIP) assays confirmed direct binding of SREBF2 to the Cav-1 promoter region.
Rescue experiments demonstrated that Cav-1 knockdown abrogated SREBF2-induced mitochondrial protection and cytoprotection.
Cav-1 thus acts as a transcriptional target of SREBF2 and a mediator of downstream PINK1/Parkin mitophagy signaling.
This positions the SREBF2→Cav-1→PINK1/Parkin axis as the mechanistic pathway linking transcriptional regulation to mitophagy and ferroptosis outcomes.
Results
Cav-1 knockdown or mitophagy inhibition abrogated the cardioprotective effects conferred by SREBF2 overexpression.
Genetic knockdown of Cav-1 reversed SREBF2-mediated improvements in mitochondrial membrane potential, mitoROS, and ferroptosis markers.
Pharmacological or genetic inhibition of mitophagy similarly abolished SREBF2-induced cytoprotection.
These loss-of-function experiments confirm the epistatic relationship: SREBF2 acts upstream of Cav-1, which acts upstream of PINK1/Parkin mitophagy.
What This Means
This research suggests that a protein called SREBF2 plays a critical protective role in heart failure that develops after a heart attack. The researchers found that SREBF2 levels are abnormally low in failing heart tissue — both in human heart failure samples and in mouse models of heart attack. When they artificially increased SREBF2 levels in mice with heart failure, the hearts functioned better, showed less scarring, and had smaller areas of dead tissue. At the cellular level, SREBF2 appeared to protect heart muscle cells from two damaging processes: a form of cell death called ferroptosis (driven by iron-dependent oxidative damage) and dysfunction of mitochondria, the energy-producing compartments of cells.
The study also traced the molecular pathway by which SREBF2 provides this protection. SREBF2 works by switching on the gene for another protein called Caveolin-1 (Cav-1), which in turn activates a cellular housekeeping process called mitophagy — essentially the cell's system for identifying and disposing of damaged mitochondria via a pathway involving proteins called PINK1 and Parkin. When the researchers blocked either Cav-1 or the mitophagy process, the protective effects of SREBF2 disappeared, confirming that this chain of events (SREBF2 → Cav-1 → PINK1/Parkin mitophagy → less ferroptosis) is the key mechanism at work.
This research suggests that boosting SREBF2 activity — or targeting any step in this newly identified pathway — could represent a novel approach to treating ischemic heart failure. By simultaneously addressing mitochondrial quality control and iron-driven cell death, therapies aimed at this axis might help preserve heart muscle in patients who have suffered a heart attack, though further research would be needed to translate these findings from animal models to human treatments.
Li J, Liu J, Luo F, Zhang C, Hu W, Liu W. (2026). SREBF2 promotes mitophagy and protects against ferroptosis via Cav-1-regulated PINK1/Parkin signaling in ischemic heart failure.. Journal of molecular medicine (Berlin, Germany). https://doi.org/10.1007/s00109-026-02707-4