PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation

Peixiang Zheng; Zhiqiang Hu; Yuli Shen; Lina Gu; Yuan Ouyang; Yuran Duan; Guimei Ji; Bofei Dong; Yanni Lin; Ting Wen; Qi Tian; Yueru Hou; Qimin Zhou; Xue Sun; Xiaohan Chen; Katherine L Wang; Shudi Luo; Shiqi Wu; Yuening Sun; Min Li; Liwei Xiao; Qingang Wu; Ying Meng; Guijun Liu; Zheng Wang; Xueli Bai; Shengzhong Duan; Yuan Ding; Yanli Bi; Yuhao Wang; Gaopeng Li; Xiaoguang Liu; Zhimin Lu; Xiaohong Wu; Zhiyuan Tang; Daqian Xu

doi:10.1038/s41589-025-01887-3

PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation

Nat Chem Biol. 2025 Sep;21(9):1420-1432. doi: 10.1038/s41589-025-01887-3. Epub 2025 Apr 25.

Authors

Peixiang Zheng^#^{1

2}, Zhiqiang Hu^#^{1

2}, Yuli Shen^#^{1

2}, Lina Gu^#³, Yuan Ouyang^{4

5}, Yuran Duan^{1

2}, Guimei Ji^{1

2}, Bofei Dong^{1

2}, Yanni Lin^{1

2}, Ting Wen^{1

2}, Qi Tian^{1

2}, Yueru Hou^{1

2}, Qimin Zhou⁶, Xue Sun⁷, Xiaohan Chen⁷, Katherine L Wang⁸, Shudi Luo^{1

2}, Shiqi Wu^{1

2}, Yuening Sun⁹, Min Li^{1

2}, Liwei Xiao^{1

2}, Qingang Wu^{1

2}, Ying Meng^{1

2}, Guijun Liu^{1

2}, Zheng Wang^{1

2}, Xueli Bai¹⁰, Shengzhong Duan¹¹, Yuan Ding¹², Yanli Bi¹³, Yuhao Wang^{1

2}, Gaopeng Li¹⁴, Xiaoguang Liu¹⁵, Zhimin Lu^{1

2}, Xiaohong Wu¹⁶, Zhiyuan Tang¹⁷, Daqian Xu^{18

19

20}

Affiliations

¹ Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
² Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, China.
³ Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
⁴ Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
⁶ Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Department of Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
⁸ St. Agnes Academy, Houston, TX, USA.
⁹ Department of Pharmacy, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.
¹⁰ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
¹¹ Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China.
¹² Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹³ Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China.
¹⁴ Department of Colorectal Surgery and Oncology of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
¹⁵ Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
¹⁶ NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, Harbin, China. wuxiaohong@hrbmu.edu.cn.
¹⁷ Department of Pharmacy, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China. tzy@ntu.edu.cn.
¹⁸ Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. xudaqian@zju.edu.cn.
¹⁹ Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, China. xudaqian@zju.edu.cn.
²⁰ NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China. xudaqian@zju.edu.cn.

^# Contributed equally.

PMID: 40281343
DOI: 10.1038/s41589-025-01887-3

Abstract

Tumor cells adapt to the inflammatory tumor microenvironment (TME) and develop resistance to immunotherapy, with ferroptosis being a major form of tumor cell death. However, the mechanisms by which tumor cells coordinate TME stimuli and their unique metabolic traits to evade ferroptosis and develop resistance to immunotherapy remain unclear. Here we showed that interferon-γ (IFNγ)-activated calcium/calmodulin-dependent protein kinase II phosphorylates phosphoserine aminotransferase 1 (PSAT1) at serine 337 (S337), allowing it to interact with glutathione peroxidase 4 (GPX4) and stabilize the protein, counteracting ferroptosis. PSAT1 elevates GPX4 stability by promoting α-ketoglutarate-dependent PHD3-mediated GPX4 proline 159 (P159) hydroxylation, disrupting its binding to HSC70 and inhibiting autophagy-mediated degradation. In mice, reconstitution of PSAT1 S337A or GPX4 P159A promotes ferroptosis and suppresses triple-negative breast cancer (TNBC) progression. Blocking PSAT1 pS337 with CPP elevates IFNγ-induced ferroptosis and enhances the efficacy of programmed cell death protein 1 (PD-1) antibodies in TNBC. Additionally, PSAT1-mediated GPX4 hydroxylation correlates with poor immunotherapy outcomes in patients with TNBC, highlighting PSAT1's noncanonical role in suppressing ferroptosis and immunotherapy sensitivity.

MeSH terms

Animals
Cell Line, Tumor
Female
Ferroptosis* / drug effects
Humans
Hydroxylation
Immunotherapy*
Interferon-gamma
Mice
Phospholipid Hydroperoxide Glutathione Peroxidase* / metabolism
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology
Triple Negative Breast Neoplasms* / therapy
Tumor Microenvironment

Substances

Phospholipid Hydroperoxide Glutathione Peroxidase
Interferon-gamma