Pharmacological activation of vitamin D receptor by paricalcitol attenuates ferroptosis-associated myocardial injury after ischemia-reperfusion.

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and characterized by oxidative damage to membrane phospholipids. Increasing evidence indicates that ferroptosis contributes to myocardial ischemia-reperfusion injury (MIRI), a condition that worsens cardiac damage following restoration of blood flow to the ischemic myocardium. This study aimed to investigate the role of ferroptosis in MIRI and to determine whether pharmacological activation of the vitamin D receptor (VDR) by paricalcitol modulates ferroptosis-associated cardiac injury. Myocardial ischemia-reperfusion was induced in mice by transient ligation of the left anterior descending coronary artery followed by reperfusion. Cardiac function was evaluated by cardiac magnetic resonance imaging. Ferroptosis-related pathways were analyzed through transcriptional profiling of antioxidant and iron-regulating genes, lipidomic assessment of oxidized phospholipid species, and ultrastructural mitochondrial evaluation. Complementary in vitro experiments were performed using human AC16 cardiomyocyte-like cells under ferroptotic stress. Ischemia-reperfusion led to a sustained deterioration of cardiac structure and function and induced several alterations consistent with ferroptosis activation, including changes in ferroptosis-related gene expression, accumulation of oxidized phospholipid species, and mitochondrial structural abnormalities. Pharmacological activation of VDR by paricalcitol attenuated ferroptosis-related transcriptional alterations, reduced lipid peroxidation, and mitigated mitochondrial structural damage, collectively limiting ferroptosis-associated cardiomyocyte injury and early ventricular dilation and systolic dysfunction. These findings suggest that VDR activation limits ferroptosis-associated cardiac injury during myocardial ischemia-reperfusion and may represent a pharmacologically relevant strategy to mitigate cardiac damage linked to ferroptosis.