Peroxisome Biogenesis Factor 10 Upregulation Promotes Cardiomyocyte Ferroptosis and Glutathione Peroxidase 4 Repression During Myocardial Ischemia-Reperfusion Injury

Objectives    Myocardial ischemia-reperfusion (I / R) injury is a major clinical challenge, largely caused by oxidative stress-induced cardiomyocyte death. Ferroptosis, an iron-dependent form of regulated cell death, plays a key role in this process, but its upstream modulators remain unclear. This study aimed to investigate the role of PEX10, a peroxisomal biogenesis factor, in ferroptosis during myocardial I / R injury.
Material and methods        Peroxisome biogenesis factor 10 (PEX10) expression was analyzed in the GSE4105 dataset and validated in H9c2 cells subjected to oxygen-glucose deprivation / reoxygenation (OGD / R). PEX10 was silenced using siRNA, and cell viability, oxidative stress, iron accumulation, and ferroptosis-related markers were measured. Glutathione peroxidase 4 (GPX4) transcriptional regulation was examined, and rescue experiments were conducted using the GPX4 inhibitor RSL3. Ferrostatin-1 was used to pharmacologically inhibit ferroptosis.
Results     PEX10 was significantly upregulated in I / R-injured myocardium and OGD / R-treated cardiomyocytes. PEX10 knockdown improved cell viability and reduced oxidative stress, iron accumulation, and ferroptosis markers. Mechanistically, PEX10 suppressed GPX4 transcription, and the protective effects of its silencing were partially reversed by RSL3 (RAS-selective lethal). Ferrostatin-1 mimicked the protective effects of PEX10 knockdown.
Conclusion    PEX10 acts as a previously unrecognized mediator of ferroptosis by repressing GPX4 transcription. Targeting the PEX10–GPX4 axis may provide a promising therapeutic strategy for mitigating myocardial I / R injury.

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