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However, the drivers of lipid metabolic dysregulation in PCa remain incompletely defined. Through transcriptomic sequencing of PCa patient tissues, we identified glutathione S\u2010transferase mu 4 (GSTM4) as a novel regulator of lipid metabolism. GSTM4 was significantly downregulated in PCa tissues and negatively correlated with triglyceride content. Functionally, GSTM4 overexpression inhibited PCa cell proliferation and migration, thereby suppressing tumor development and bone metastasis. Mechanistically, GSTM4 acted independently of its classical detoxification activity by interacting with tripartite motif\u2010containing 27 (TRIM27) and ATP citrate lyase (ACLY), a key enzyme in de novo lipid synthesis. GSTM4 promoted TRIM27\u2010mediated ubiquitination and degradation of ACLY at lysine 554, reducing acetyl\u2010CoA production and lipid accumulation. This inhibition of lipid synthesis suppressed PCa growth and metastasis in vitro and in subcutaneous, orthotopic, and bone metastasis models. Moreover, ETC\u20101002 (bempedoic acid), a clinically approved ACLY inhibitor, showed therapeutic potential against PCa. These findings reveal a non\u2010canonical GSTM4\u2010TRIM27\u2010ACLY axis that regulates lipid metabolism and represents a promising therapeutic target for advanced PCa.<\/jats:p>","DOI":"10.1002\/advs.77394","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T03:10:25Z","timestamp":1788145825000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GSTM4 Suppresses Prostate Cancer Progression by Targeting TRIM27\u2010mediated ACLY Ubiquitination and Lipid Metabolism"],"prefix":"10.1002","author":[{"given":"Kang\u2010Ping","family":"Xiong","sequence":"first","affiliation":[{"name":"Department of Medical Oncology The First Affiliated Hospital Jiangxi Medical College Nanchang University  Nanchang China"},{"name":"Department of Urology Hubei Key Laboratory of Urological Diseases Zhongnan Hospital of Wuhan University  Wuhan 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