SREBF2 protects failing hearts from ferroptosis via Cav-1-regulated PINK1/Parkin mitophagy

A Cholesterol-Regulating Gene May Shield Injured Hearts From a Dangerous Form of Cell Death

A gene best known for controlling cholesterol production has emerged as a potential defender against the chain of mitochondrial damage that drives heart failure after a heart attack. In a study published in the Journal of Molecular Medicine, researchers report that SREBF2 helps damaged heart cells remove defective mitochondria and resist ferroptosis, an iron-dependent form of cell death increasingly linked to cardiovascular injury. The protection depended on a molecular pathway involving caveolin-1, or Cav-1, and the mitochondrial quality-control proteins PINK1 and Parkin. In mice, increasing SREBF2 activity improved cardiac function, reduced the size of infarcted tissue and limited fibrosis after myocardial infarction. The findings point to a previously unrecognized connection between lipid regulation, mitochondrial recycling and the long-term deterioration of the heart following an ischemic event. They also suggest that restoring this pathway could eventually provide a new strategy for treating ischemic heart failure, although the work remains preclinical and does not yet establish a therapy for patients.

Heart failure following myocardial infarction remains a major cause of cardiovascular illness and death. A blocked coronary artery deprives cardiac muscle of oxygen, and even when blood flow is restored, the sudden return of oxygen can intensify oxidative stress and injure cells that survived the initial ischemic episode. Over time, the heart may enlarge, stiffen and replace lost muscle with scar tissue, a process known as adverse remodeling. The researchers focused on ferroptosis because it differs from more familiar forms of cell death. Rather than being driven primarily by caspases or by the orderly dismantling characteristic of apoptosis, ferroptosis results from the accumulation of iron and the uncontrolled oxidation of polyunsaturated fatty acids in cell membranes. As lipid peroxides build up, membranes lose their integrity. The antioxidant enzyme GPX4 normally prevents this damage by using reduced glutathione, or GSH, to convert lipid peroxides into less harmful molecules. When this defense fails, iron-catalyzed chemistry can push the cell beyond repair.

To search for regulators of this process in post-infarction heart failure, the team first analyzed the GSE24519 gene-expression dataset and compared differentially expressed genes with genes associated with ferroptosis. SREBF2 stood out as a candidate. The gene encodes sterol regulatory element-binding protein 2, a transcription factor classically associated with cholesterol homeostasis. In its active form, SREBF2 enters the nucleus and binds DNA sequences that control genes involved in sterol synthesis and uptake. The new results indicate that its influence extends beyond cholesterol metabolism. SREBF2 was significantly reduced in human heart-failure samples, in mouse hearts subjected to myocardial infarction and heart-muscle cells exposed to oxygen-glucose deprivation, a laboratory model of ischemic stress. The convergence of observations across human tissue, animals and cultured cardiomyocytes strengthened the case that SREBF2 responds to clinically relevant cardiac injury rather than being an incidental signal in a single experimental system.

The researchers then increased SREBF2 expression in mice after inducing myocardial infarction. Compared with injured animals lacking the intervention, mice with elevated SREBF2 showed improved measures of cardiac performance, smaller infarct regions and less fibrosis. Fibrosis is the excessive deposition of structural proteins such as collagen that can preserve the shape of damaged tissue but also make the ventricle less elastic and disrupt electrical and mechanical coordination. The reported improvements were accompanied by evidence of more favorable myocardial remodeling. In cultured cardiomyocytes, SREBF2 overexpression also reduced the biochemical signature of ferroptosis. Levels of reactive oxygen species, malondialdehyde and ferrous iron were lower, while GSH and GPX4 were restored. ACSL4, an enzyme that helps incorporate vulnerable polyunsaturated fatty acids into membrane lipids and is widely used as a ferroptosis-associated marker, was reduced. Together, these changes indicate that SREBF2 did not merely improve a general stress response; it shifted the cells away from the chemical conditions that allow iron-driven lipid damage to escalate.

The central clue came from the mitochondria, the organelles that generate most of a cardiomyocyte’s ATP. Heart-muscle cells rely heavily on oxidative phosphorylation, so damaged mitochondria can rapidly become a liability: they produce excessive reactive oxygen species, lose their electrochemical gradient and amplify metabolic stress. The study found that SREBF2 improved mitochondrial membrane potential, denoted ΔΨm, while reducing mitochondrial reactive oxygen species. It also helped rebalance mitochondrial dynamics, the continual cycle of fission and fusion that allows the organelles to distribute energy, isolate damaged segments and maintain a functional network. ΔΨm is a measure of the voltage across the inner mitochondrial membrane, created as electrons move through the respiratory chain and protons are pumped across it. A collapse in this potential signals impaired energy conversion and can promote further oxidative injury. By preserving ΔΨm and reducing mitoROS, SREBF2 appeared to interrupt a feedback loop in which mitochondrial failure fuels ferroptosis and ferroptosis, in turn, worsens mitochondrial damage.

The proposed repair mechanism is mitophagy, the selective form of autophagy that identifies and removes defective mitochondria. In the pathway examined by the researchers, damaged mitochondria accumulate the kinase PINK1 on their outer membrane. PINK1 then helps recruit and activate the ubiquitin ligase Parkin, which marks the impaired organelle for engulfment by autophagic membranes and delivery to lysosomes for degradation. This process is not simply cellular housekeeping. In highly active tissues such as the heart, effective mitophagy prevents dysfunctional mitochondria from remaining in the network and generating toxic oxidants. SREBF2 increased the activity of the PINK1/Parkin system and altered levels of mitophagy-related proteins, including p62, a cargo-adaptor protein that helps connect ubiquitinated material to the autophagic machinery. The findings suggest that the gene protects cardiomyocytes partly by improving the removal of damaged mitochondria before they become major sources of oxidative and iron-related injury.

The investigators next traced the signal upstream to Cav-1, the protein encoded by the CAV1 gene. Cav-1 is a structural component of caveolae, small, flask-shaped invaginations in the plasma membrane that organize receptors, enzymes and signaling complexes. Although it has established roles in vascular biology and mechanosensation, the study identifies Cav-1 as a necessary link between SREBF2 and mitochondrial quality control in ischemic heart failure. Chromatin immunoprecipitation experiments indicated that SREBF2 directly binds regulatory DNA associated with CAV1 and transcriptionally activates the gene. In other words, SREBF2 appears to function as a molecular switch: after increasing Cav-1 production, it promotes signaling that activates PINK1/Parkin-mediated mitophagy. This places a transcription factor traditionally connected with sterol regulation at the top of a pathway that reaches from the nucleus to the plasma membrane and finally to mitochondrial disposal.

The strongest evidence for this model came from the study’s rescue experiments. When Cav-1 was knocked down, the mitochondrial benefits associated with SREBF2 were lost. Mitophagy inhibition likewise abolished much of the protection against ferroptosis and cellular injury. These interventions reduced the improvement in mitochondrial membrane potential and restored the conditions associated with oxidative damage, including elevated reactive oxygen species and impaired antioxidant defenses. Such experiments are important because they test whether a molecular correlation is functionally required. If SREBF2 were acting through an unrelated antioxidant pathway, disabling Cav-1 or mitophagy should not have erased its effects. Instead, the results support a sequence in which reduced SREBF2 after infarction weakens Cav-1 transcription, suppresses PINK1/Parkin-dependent mitochondrial clearance and leaves cardiomyocytes vulnerable to ferroptosis. The pathway is likely more complex than a single linear chain, but the dependency experiments give the proposed axis—SREBF2, Cav-1, PINK1/Parkin and mitophagy—a mechanistic foundation.

The discovery also raises a therapeutic question: can SREBF2 be manipulated safely in the injured heart? Because SREBF2 is deeply involved in cholesterol synthesis and uptake, increasing its activity throughout the body could have unintended effects on lipid levels or vascular disease risk. The researchers’ results do not show that activating SREBF2 is safe in humans, nor do they establish whether the gene can be targeted selectively in cardiomyocytes after an infarction. The experiments used myocardial-infarction mice, oxygen-glucose-deprived cultured cardiomyocytes and human heart-failure samples, but the report does not describe a clinical trial or a drug capable of selectively turning on the pathway. Future work will need to determine how SREBF2 is downregulated after ischemic injury, whether Cav-1 can be targeted more directly, and how much mitophagy is beneficial before excessive mitochondrial turnover becomes harmful. It will also be important to test the mechanism in larger animals and across different causes and stages of heart failure. For now, the study offers a striking biological insight: a cholesterol-sensing transcription factor may help the heart survive by sending damaged mitochondria to the cellular recycling system, thereby preventing iron-fueled membrane destruction from turning injury into progressive cardiac failure.