Journal Article

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

Cai, Yun, Wang, Cenzhu, Wang, Fengxu, Li, Qi, Qian, Zhiwen, Gao, Erli, Zhao, Xinyuan, Wang, Yida, Gu, Yanfang, Wu, Danping, Ning, Xin, You, Yilan, Dong, Jianfeng, Jiang, Ying, Mei, Jie, Zhang, Yan, Liu, Lu, Zhang, Feng

2025

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Apoptosis / Biomedical and Life Sciences / Biomedicine / Biosynthesis / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer Research / Cancer therapies / Cell death / Cell Line, Tumor / Chemotherapy / Cold / Enzymes / FASN / Fatty Acid Synthase, Type I - genetics / Fatty Acid Synthase, Type I - metabolism / Fatty acids / Female / Ferroptosis / Health aspects / Humans / Immunology / Immunotherapy / Ligases / Lipids / Lipoylation / Lymphatic system / Medical prognosis / Medical research / Medicine, Experimental / Metabolism / Metastasis / Mice / Oncology / Palmitoylation / Peroxidase / Phospholipid Hydroperoxide Glutathione Peroxidase - genetics / Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism / Physiological aspects / Proteases / Proteins / Synthesis / Tumors / Ubiquitin-proteasome system / Ubiquitination / USP5