GSTM4 Suppresses Prostate Cancer Progression by Targeting TRIM27‐mediated ACLY Ubiquitination and Lipid Metabolism
9 affiliations
- 1Department of Medical Oncology The First Affiliated Hospital Jiangxi Medical College Nanchang University Nanchang China
- 2Department of Urology Hubei Key Laboratory of Urological Diseases Zhongnan Hospital of Wuhan University Wuhan China
- 3National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
- 4Institute of Urology Wuhan University Wuhan China
- 5Department of Biological Repositories Human Genetic Resource Preservation Center of Hubei Province Zhongnan Hospital of Wuhan University Wuhan China
- 6Department of Obstetrics and Gynecology Ultrasound Zhongnan Hospital of Wuhan University Wuhan China
- 7Center For Evidence‐Based and Translational Medicine Zhongnan Hospital of Wuhan University Wuhan China
- 8Medical Research Institute Frontier Science Center for Immunology and Metabolism Taikang Center for Life and Medical Sciences Wuhan University Wuhan China
- 9Wuhan Research Center for Infectious Diseases and Cancer Chinese Academy of Medical Sciences Wuhan China
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.
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BibTeX
@article{xiong2026gstm4,
title = {{GSTM4 Suppresses Prostate Cancer Progression by Targeting TRIM27‐mediated ACLY Ubiquitination and Lipid Metabolism}},
author = {Kang‐Ping Xiong and Fei Liu and Wang Wang and Gang Wang and Kai‐Yu Qian and Sheng Tu and Si‐Ming Chen and Hui‐Min Xu and Shan‐Shan Zhang and Yong Li and Xing‐Huan Wang and Hong Weng},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77394},
url = {https://doi.org/10.1002/advs.77394},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - GSTM4 Suppresses Prostate Cancer Progression by Targeting TRIM27‐mediated ACLY Ubiquitination and Lipid Metabolism
AU - Kang‐Ping Xiong
AU - Fei Liu
AU - Wang Wang
AU - Gang Wang
AU - Kai‐Yu Qian
AU - Sheng Tu
AU - Si‐Ming Chen
AU - Hui‐Min Xu
AU - Shan‐Shan Zhang
AU - Yong Li
AU - Xing‐Huan Wang
AU - Hong Weng
PY - 2026
DA - 2026/08/30
JO - Advanced Science
DO - 10.1002/advs.77394
UR - https://doi.org/10.1002/advs.77394
AB - 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.
SN - 2198-3844
ER -