{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:48:08Z","timestamp":1791589688265,"version":"4.3.4"},"reference-count":140,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009110","name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","doi-asserted-by":"crossref","award":["2025D01C56"],"award-info":[{"award-number":["2025D01C56"]}],"id":[{"id":"10.13039\/100009110","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009110","name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","doi-asserted-by":"crossref","award":["2024D01C58"],"award-info":[{"award-number":["2024D01C58"]}],"id":[{"id":"10.13039\/100009110","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Undergraduate Innovation Training Program of Xinjiang University","award":["202510755105"],"award-info":[{"award-number":["202510755105"]}]},{"award":["202510755105"],"award-info":[{"award-number":["202510755105"]}],"id":[{"id":"https:\/\/ror.org\/059gw8r13","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Glutathione peroxidase 4 (GPX4) is canonically viewed as the primary suppressor of ferroptosis, yet its role in the tumor microenvironment (TME) extends far beyond antioxidant catalysis to encompass immuno-metabolic regulation. In this review, we synthesize recent advances in enzymology, immunology, and cancer metabolism to propose a \u201clipid peroxidation threshold\u201d framework, wherein GPX4 sets cell-type-specific thresholds that determine susceptibility to ferroptosis across tumor cells, CD8+ T cells, dendritic cells (DCs), and myeloid populations. We discuss how these thresholds are dynamically adjusted by post-translational modifications, nutrient competition and intercellular feedback loops, resulting in significant spatial heterogeneity between the tumor core and the tumor invasive front. There is a current selectivity paradox in GPX4 inhibitors, as well as resistance through nuclear factor erythroid 2-related factor 2 (Nrf2) and ferroptosis suppressor protein 1 (FSP1) that restricts the efficacy of GPX4 inhibitors as monotherapy. We focus on rational combination approaches: GPX4 modulation with immune checkpoint blockade (ICB), chemotherapy, and targeting myeloid-derived suppressor cells (MDSCs); and the pressing need for predictive biomarkers and single-cell spatial profiling. We conclude that successful clinical translation requires moving beyond indiscriminate GPX4 inhibition toward precision \u201cthreshold engineering\u201d that selectively lowers tumor lipid peroxidation thresholds while sparing immune cells.<\/jats:p>","DOI":"10.3390\/biom16071006","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T09:46:47Z","timestamp":1783676807000},"page":"1006","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["GPX4 in the Tumor Microenvironment: Not Just Inhibiting Ferroptosis, but Immuno-Metabolic Regulation"],"prefix":"10.3390","volume":"16","author":[{"given":"Xinzhe","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmacy & Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"},{"name":"College of Life Science and Technology, Xinjiang University, Urumqi 830046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manxuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy & Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"},{"name":"College of Life Science and Technology, Xinjiang University, Urumqi 830046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4806-8261","authenticated-orcid":false,"given":"Zenan","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmacy & Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"},{"name":"College of Life Science and Technology, Xinjiang University, Urumqi 830046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reziyamu","family":"Wufuer","sequence":"additional","affiliation":[{"name":"School of Pharmacy & Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"},{"name":"College of Life Science and Technology, Xinjiang University, Urumqi 830046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0436-4277","authenticated-orcid":false,"given":"Wenfang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy & Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"},{"name":"College of Life Science and Technology, Xinjiang University, Urumqi 830046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.freeradbiomed.2020.02.027","article-title":"Lipid peroxidation and ferroptosis: The role of GSH and GPx4","volume":"152","author":"Ursini","year":"2020","journal-title":"Free Radic. 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