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The anti\u2010GBC effects of \u03c9\u20103PUFAs (DHA\/EPA) were evaluated using in vitro assays and mouse xenograft models. Epigenetic changes were analyzed by RRBS, MSP, and MethyLight PCR. Downstream mechanisms were explored via proteomics, Co\u2010IP, and Western blot. This study demonstrates that \u03c9\u20103PUFAs suppress GBC progression by inducing promoter hypermethylation of STK31, which is an oncogene found in GBC by our previous study. MethyLight PCR revealed that \u03c9\u20103PUFAs treatment significantly increased STK31 promoter methylation in GBC\u2010SD cells from 34.1%\u00a0\u00b1\u00a020.91% to 89.1%\u00a0\u00b1\u00a013.11%. Moreover, STK31(DNMT1)\/GSK3\u03b2 pathway and COL4A1 (ITGB1) were particularly associated with \u03c9\u20103PUFAs' inhibitory mechanisms to GBC. In vivo experimental results demonstrated that \u03c9\u20103PUFAs significantly inhibited the growth of gallbladder cancer xenografts, with tumor growth inhibition rates of 38.6% for GBC\u2010SD and 50.2% for NOZ at day 33, and effectively suppressed tumor cell\u00a0metastasis in an intraperitoneal mouse model. This study provides first evidence that \u03c9\u20103PUFAs target STK31 via epigenetic reprogramming, opening new avenues for dietary intervention and targeted therapy of GBC.<\/jats:p>","DOI":"10.1002\/mnfr.70522","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T06:11:26Z","timestamp":1781244686000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["\u03c9\u20103PUFAs Inhibit Gallbladder Cancer Through Enhancing STK31 Methylation"],"prefix":"10.1002","volume":"70","author":[{"given":"Shuang\u2010Xing","family":"Li","sequence":"first","affiliation":[{"name":"Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University  Kunming Yunnan Province China"},{"name":"Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province  Kunming Yunnan Province China"},{"name":"Kunming Medical University  Kunming Yunnan Province 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Affiliated to Kunming Medical University  Kunming Yunnan Province China"},{"name":"Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province  Kunming Yunnan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"He","sequence":"additional","affiliation":[{"name":"Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University  Kunming Yunnan Province China"},{"name":"Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province  Kunming Yunnan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University  Kunming Yunnan Province China"},{"name":"Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province  Kunming Yunnan Province 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