GSTM4 Suppresses Prostate Cancer Progression by Targeting TRIM27‐mediated ACLY Ubiquitination and Lipid Metabolism

Abstract

ABSTRACT Prostate cancer (PCa) is a prevalent malignancy in men, and lipid metabolic reprogramming contributes to its progression and therapeutic resistance. However, the drivers of lipid metabolic dysregulation in PCa remain incompletely defined. Through transcriptomic sequencing of PCa patient tissues, we identified glutathione S‐transferase 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‐containing 27 (TRIM27) and ATP citrate lyase (ACLY), a key enzyme in de novo lipid synthesis. GSTM4 promoted TRIM27‐mediated ubiquitination and degradation of ACLY at lysine 554, reducing acetyl‐CoA 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‐1002 (bempedoic acid), a clinically approved ACLY inhibitor, showed therapeutic potential against PCa. These findings reveal a non‐canonical GSTM4‐TRIM27‐ACLY axis that regulates lipid metabolism and represents a promising therapeutic target for advanced PCa.