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. 2026 Sep 22;17:1935866. doi: 10.3389/fimmu.2026.1935866

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Copyright © 2026 Xu, He, Feng, Cai, Zhao, Xin, Zhang, Qin and Wang.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Illustration depicting how ionizing radiation induces ferroptosis in testicular cells. It shows radiolysis generating reactive oxygen species (ROS), iron metabolism via ferritinophagy, Fenton reactions, and p53-mediated antioxidant depletion leading to lipid peroxidation, mitochondrial changes, membrane damage, and failure of lipid peroxidation inhibition via the FSP1 pathway. — Proposed molecular mechanisms linking ionizing radiation (IR) to ferroptosis in testicular cells. IR exposure triggers water radiolysis to generate hydroxyl radicals (·OH) and induces DNA double-strand breaks (DSBs) that activate the p53 pathway. In the iron metabolism axis, NCOA4-mediated ferritinophagy promotes the degradation of ferritin (FTH/FTL) by lysosomal enzymes, releasing abundant Fe²⁺ into the labile iron pool (LIP). This free iron is transported into mitochondria via VDAC2/3, driving the Fenton reaction (Fe²⁺ + H₂O₂ → ·OH + OH^- + Fe³⁺), which exacerbates ROS production, and induces characteristic mitochondrial structural changes (increased membrane density and reduced cristae). Meanwhile, in the p53/antioxidant axis, activated p53 transcriptionally inhibits the System Xc^- core subunit SLC7A11, leading to glutathione (GSH) depletion and subsequent inactivation of GPX4. Furthermore, downregulation of the FSP1 pathway (with decreased CoQ10 levels) results in a failure to inhibit lipid peroxidation. Collectively, the convergence of iron overload, ROS accumulation, and impaired GPX4- and FSP1-dependent antioxidant defenses could promote severe lipid peroxidation of membrane PUFAs and thereby increase susceptibility to ferroptotic membrane damage. Some graphical elements were created with BioRender.com.