What question did this study set out to answer?

This research aims to identify how the deletion of GPX8 affects sensitivity to radiation and ferroptosis in oral cancer cells.

May 21, 2026

Deletion of GPX8 Enhances Irradiation-Induced Ferroptosis Through m 6 A Hypomethylation-Mediated Upregulation of ACSL4 in Oral Cancer

Puntos clave

This research aims to identify how the deletion of GPX8 affects sensitivity to radiation and ferroptosis in oral cancer cells.
Investigated GPX8's role in radiosensitivity and ferroptosis mechanisms in oral cancer cell lines.
Utilized an orthotopic xenograft model to observe effects on tumor growth and radiosensitivity.
Analyzed the impact of oxidative stress on E2F4 and ZC3H13 expression and ACSL4 stability.
GPX8 deletion significantly increased IR-induced ferroptotic cell death, evidenced by elevated lipid peroxidation and reactive oxygen species.
Knockout tumors showed enhanced radiosensitivity with increased ferroptosis markers and mitigated by liproxstatin-1.
E2F4 overexpression reversed ACSL4 upregulation, confirming the regulatory pathway's role.

Resumen

Aims: Radioresistance limits the therapeutic efficacy of radiotherapy, and although ferroptosis contributes to radiation-induced tumor suppression, the upstream redox-epitranscriptomic mechanisms remain poorly defined. 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. Results: 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 6 -methyladenine (m 6 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. Innovation: This work uncovers a previously uncharacterized antioxidant–m 6 A–ferroptosis regulatory pathway and provides the first evidence that GPX8 modulates radiotherapy response by epitranscriptomic control of ACSL4 stability via the E2F4–ZC3H13 axis. Conclusion: GPX8 deletion sensitizes oral cancer to irradiation by promoting ferroptosis through oxidative stress-driven suppression of E2F4 and ZC3H13, resulting in m 6 A hypomethylation and stabilization of ACSL4 mRNA. GPX8 thus represents a promising target for ferroptosis-based radiosensitization. Antioxid. Redox Signal. 00, 000–000.

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Cite This Study

Chen et al. (Tue,) studied this question.

synapsesocial.com/papers/6a0ea17cbe05d6e3efb601e7 https://doi.org/https://doi.org/10.1177/15230864261449406

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