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However, chemotherapy resistance, compounded by increased stemness, poses a significant challenge in GC management. In this study, we demonstrate that JMJD3, encoded by\n                    <jats:italic>KDM6B<\/jats:italic>\n                    and catalyzing the demethylation of H3K27me3, is highly expressed in both GC tissues and patient-derived chemotherapy-resistant xenograft (PDX) models and contributes to increased malignancy and chemoresistance. Overexpression of JMJD3 enhanced stemness and chemoresistance in GC cells, while JMJD3 knockdown had opposite effects. Mechanistically, JMJD3 promotes GC cell stemness and chemoresistance by reducing H3K27me3 on the\n                    <jats:italic>ALOX5<\/jats:italic>\n                    promoter, a histone modification associated with ALOX5 transcriptional activation. Tumorigenesis induced by N-methyl-N-nitrosourea (MNU) was reduced in mice with gastric epithelial cell-specific deletion of\n                    <jats:italic>Kdm6b<\/jats:italic>\n                    . Importantly, ALOX5 upregulation due to the elevated JMJD3 function sensitized GC cells to ferroptosis inducers. These findings suggest that JMJD3 plays a pivotal role in GC chemoresistance by modulating both stemness and ferroptosis sensitivity. Targeting JMJD3 may provide a novel therapeutic strategy for overcoming chemotherapy resistance, with ferroptosis inducers potentially offering a promising adjunctive treatment in GC.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08020-1","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T14:05:45Z","timestamp":1762178745000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["JMJD3 upregulates ALOX5 to drive malignancy and concomitant ferroptosis sensitivity in gastric cancer"],"prefix":"10.1038","volume":"16","author":[{"given":"Gege","family":"Shu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaoyang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8503-4071","authenticated-orcid":false,"given":"Anqi","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weikang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengbo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2618-9342","authenticated-orcid":false,"given":"Changshun","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6829-6149","authenticated-orcid":false,"given":"Jin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"8020_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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