{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T11:04:12Z","timestamp":1790247852836,"version":"4.1.0"},"reference-count":175,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Lung cancer is one of the most prevalent and lethal malignancies worldwide, and radiotherapy serves as a standard therapeutic modality for the management of advanced or inoperable non-small cell lung cancer. However, radioresistance remains a major obstacle that compromises therapeutic efficacy and drives tumor recurrence. Ferroptosis\u2014an iron-dependent, lipid peroxidation-governed form of regulated cell death\u2014substantially contributes to radiation-mediated tumor cell elimination. This review establishes a multi-layered regulatory network through which ferroptosis mediates radioresistance in lung cancer, spanning genetic mutations, epigenetic and RNA-based regulation, protein post-translational modifications, and lipid metabolism reprogramming. Unlike existing reviews, this paper stratifies ferroptotic vulnerability and radiosensitivity according to common driver genotypes\u2014including TP53, LKB1and KEAP1\u2014and proposes a genotype-guided paradigm for precise radiosensitization. By integrating these molecular layers, review provides a supplementary theoretical framework for optimizing radiotherapy in lung cancer and highlights how targeting ferroptosis can overcome resistance in a mutation-specific manner. Furthermore, the crosstalk between ferroptosis and cuproptosis represents a promising combinatorial therapeutic avenue that warrants further preclinical and clinical investigation.<\/jats:p>","DOI":"10.3389\/fcell.2026.1886712","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:15:53Z","timestamp":1790244953000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Geno-guided targeting of ferroptosis: a multi-layered network to overcome radioresistance in lung cancer"],"prefix":"10.3389","volume":"14","author":[{"given":"Shifang","family":"Sang","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, The First Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangchao","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The First Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyun","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The First Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, College of Basic Medical Sciences, Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The First Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianlong","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The First Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaizhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The First Hospital of Jilin University","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"123675","DOI":"10.1016\/j.biomaterials.2025.123675","article-title":"Engineering ferroptosis radiosensitizer for SPARC-targeted degradation: a strategy to reverse radioresistant non-small cell lung cancer","volume":"326","author":"Aishajiang","year":"2026","journal-title":"Biomaterials"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3464","DOI":"10.3390\/cells11213464","article-title":"Mitoferrin, cellular and mitochondrial iron homeostasis","volume":"11","author":"Ali","year":"2022","journal-title":"Cells"},{"key":"B3","doi-asserted-by":"publisher","first-page":"112946","DOI":"10.1016\/j.yexcr.2021.112946","article-title":"Hemin enhances radiosensitivity of lung cancer cells through ferroptosis","volume":"410","author":"Almahi","year":"2022","journal-title":"Exp. 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