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This study investigated how loss of the antioxidant enzyme glutathione peroxidase 8 (GPX8) influences susceptibility to ionizing radiation (IR), delineated the molecular pathway linking oxidative stress to ferroptosis, and evaluated the potential of GPX8 deletion as a radiosensitization strategy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      We identify GPX8 as a previously unrecognized suppressor of ferroptosis whose deletion markedly amplifies IR-induced ferroptotic cell death. GPX8 deficiency increased reactive oxygen species accumulation, lipid peroxidation, labile iron levels, and ferroptosis-associated gene expression following irradiation. Mechanistic dissection revealed a novel redox-epitranscriptomic axis: oxidative stress induced by GPX8 loss downregulated the transcription factor E2F4, which in turn reduced zinc-finger CCCH-type containing 13 (ZC3H13) expression, leading to N\n                      <jats:sup>6<\/jats:sup>\n                      -methyladenine (m\n                      <jats:sup>6<\/jats:sup>\n                      A) hypomethylation and stabilization of acyl-CoA synthetase long-chain family member 4 (ACSL4) mRNA. Overexpression of E2F4 or ZC3H13 reversed ACSL4 upregulation, confirming pathway causality. ACSL4 knockdown diminished ferroptosis and rescued the hypersensitivity of GPX8-deficient cells to IR. In an orthotopic xenograft model, GPX8-knockout tumors displayed significantly enhanced radiosensitivity and elevated ferroptotic markers, effects mitigated by the ferroptosis inhibitor liproxstatin-1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Innovation:<\/jats:title>\n                    <jats:p>\n                      This work uncovers a previously uncharacterized antioxidant\u2013m\n                      <jats:sup>6<\/jats:sup>\n                      A\u2013ferroptosis regulatory pathway and provides the first evidence that GPX8 modulates radiotherapy response by epitranscriptomic control of ACSL4 stability\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      the E2F4\u2013ZC3H13 axis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      GPX8 deletion sensitizes oral cancer to irradiation by promoting ferroptosis through oxidative stress-driven suppression of E2F4 and ZC3H13, resulting in m\n                      <jats:sup>6<\/jats:sup>\n                      A hypomethylation and stabilization of ACSL4 mRNA. GPX8 thus represents a promising target for ferroptosis-based radiosensitization.\n                      <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                      45, 219\u2013241.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/15230864261449406","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T01:54:36Z","timestamp":1779242076000},"page":"219-241","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Deletion of GPX8 Enhances Irradiation-Induced Ferroptosis Through m\n                    <sup>6<\/sup>\n                    A Hypomethylation-Mediated Upregulation of ACSL4 in Oral Cancer"],"prefix":"10.1177","volume":"45","author":[{"given":"Xun","family":"Chen","sequence":"first","affiliation":[{"name":"Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, People\u2019s Republic of 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