Fasting-mimicking diet moderates myocardial ischemia/reperfusion injury through the PCBP2-ACSL4 regulatory axis in...

Myocardial ischemia/reperfusion (I/R) injury is a major contributor to coronary heart disease. Fasting has emerged as a cardioprotective intervention, yet the underlying mechanisms are unclear. Ferroptosis, an iron-dependent form of regulated cell death, has been implicated in I/R injury, but its interplay with fasting in the myocardial context has yet to be determined. Following myocardial I/R injury, mice were fed either a normal diet or a fasting-mimicking diet (FMD). Cardiac function, myocardial damage, and ferroptosis-related parameters were assessed. H9c2 cardiomyocytes were cultured in normal medium or fasting-mimic medium (FMM) and subjected to oxygen-glucose deprivation/reoxygenation. Expression of ferroptosis markers and PCBP2 was analyzed by qRT-PCR, western blotting, and immunofluorescence. I/R injury induced ferroptosis, with altered ferroptosis-related proteins, iron accumulation, and elevated oxidative stress. FMD ameliorated myocardial I/R injury, improving cardiac function and reducing infarct size. Mechanistically, FMD was associated with AMPK/SIRT1 activation and PCBP2 downregulation. PCBP2 directly interacted with ferroptosis-related proteins, with ACSL4 as a downstream target. PCBP2 knockdown increased anti-ferroptotic factors while decreasing ACSL4, protecting cardiomyocytes from ferroptosis. ACSL4 overexpression completely abolished benefits of both PCBP2 knockdown and FMD. However, the hierarchical relationship between AMPK/SIRT1 activation and PCBP2 regulation is based on association data. Our study demonstrates that fasting inhibits ferroptosis through PCBP2 downregulation, which modulates the ACSL4-mediated ferroptosis pathway. In these preclinical models, the PCBP2/ACSL4 axis emerges as a candidate mechanism and potential therapeutic target against ferroptosis-induced myocardial I/R injury, supporting further translational evaluation of fasting intervention.