2. Academic Validation
  3. FASN inhibits ferroptosis in breast cancer via USP5 palmitoylation-dependent regulation of GPX4 deubiquitination

FASN inhibits ferroptosis in breast cancer via USP5 palmitoylation-dependent regulation of GPX4 deubiquitination

  • J Exp Clin Cancer Res. 2025 Oct 14;44(1):289. doi: 10.1186/s13046-025-03548-8.
Zhiwen Qian # 1,  Ying Jiang # 2,  Yun Cai # 3,  Erli Gao # 4,  Cenzhu Wang 5,  Jianfeng Dong 6,  Fengxu Wang 7,  Lu Liu 2,  Danping Wu 2,  Feng Zhang 1,  Yida Wang 1,  Xin Ning 2,  Qi Li 2,  Yilan You 1,  Yanfang Gu 8 9,  Jie Mei 10,  Xinyuan Zhao 11,  Yan Zhang 12 13
Affiliations

Affiliations

  • 1 Department of Oncology, Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, Jiangsu, China.
  • 2 Department of Oncology, School of Medicine, Women's Hospital of Jiangnan University, Jiangnan University, WuxiWuxi, Jiangsu, China.
  • 3 Central Laboratory, Jintan Affiliated Hospital of Jiangsu University, Changzhou, Jiangsu, People's Republic of China.
  • 4 Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 5 Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
  • 6 Department of Pathology, Affiliated Women's Hospital of Jiangnan University, Wuxi, Jiangsu, China.
  • 7 School of Public Health, Nantong University, Nantong, China.
  • 8 Department of Oncology, Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, Jiangsu, China. guyanfang2103@163.com.
  • 9 Department of Oncology, School of Medicine, Women's Hospital of Jiangnan University, Jiangnan University, WuxiWuxi, Jiangsu, China. guyanfang2103@163.com.
  • 10 The First Clinical Medicine College, Nanjing Medical University, Nanjing, Jiangsu, China. meijie1996@njmu.edu.cn.
  • 11 School of Public Health, Nantong University, Nantong, China. zhaoxinyuan@ntu.edu.cn.
  • 12 Department of Oncology, Wuxi Maternal and Child Health Hospital, Nanjing Medical University, Wuxi, Jiangsu, China. fuyou2007@126.com.
  • 13 Department of Oncology, School of Medicine, Women's Hospital of Jiangnan University, Jiangnan University, WuxiWuxi, Jiangsu, China. fuyou2007@126.com.
  • # Contributed equally.
PMID: 41088402 DOI: 10.1186/s13046-025-03548-8
Abstract

Increasing studies have reported that dysregulated lipid metabolism is an independent risk factor for breast Cancer (BC); it would be, therefore, enlightening to investigate the relationship between metabolic reprogramming and the tumor microenvironment in the future. Ferroptosis, a novel form of programmed cell death, is characterized by glutathione (GSH) depletion and inactivation of Glutathione Peroxidase 4 (GPX4), the central regulator of the antioxidant system. While the close association between fatty acid metabolism and Ferroptosis has been studied in various diseases, the interplay between the key fatty acid metabolic enzyme fatty acid synthase (FASN) and Ferroptosis in BC remains unexplored. At the beginning of the current study, we demonstrated that FASN expression positively correlates with an immune-cold tumor microenvironment in BC. Subsequent findings revealed that FASN knockdown promotes GPX4 degradation-induced Ferroptosis, thereby enhancing the efficacy of anti-programmed cell death protein 1 (PD-1) immunotherapy. Co-immunoprecipitation coupled with mass spectrometry (IP/MS) and co-IP experiments demonstrated that ubiquitin specific protease 5 (USP5) stabilizes GPX4 by binding to and deubiquitinating it. Furthermore, knockdown of FASN inhibited the palmitoylation of USP5, reducing its interaction with GPX4 and consequently increasing GPX4 ubiquitination and degradation. Our results demonstrate that FASN suppresses Ferroptosis in BC by stabilizing GPX4 via USP5-mediated mechanisms, highlighting FASN inhibition as a potential therapeutic approach to enhance immunotherapy response.

Keywords

Breast cancer; FASN; Ferroptosis; Palmitoylation; USP5.

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