TGM2-mediated serotonylation of GPX4 confers ferroptosis resistance to promote gastric tumorigenesis PMID: 42049702

ADC Targets in Oncology

2026-04-10

TGM2-mediated serotonylation of GPX4 confers ferroptosis resistance to promote gastric tumorigenesis

Cell Discov. 2026 Apr 28;12(1):30. doi: 10.1038/s41421-026-00885-6.

Junping Bai ^# ¹ , Dandan Geng ^# ² , Xinwen Chen ^# ³ , Wanting Li ^# ⁴ , Xiaowei Wang ¹ , Luyang Tian ⁵ , Yi Han ¹ , Zhao Jin ⁶ ⁷ , Meihang Du ¹ , Yang Tang ¹ , Weisheng Hu ⁸ , Chunxiao Zhu ⁵ , Shan Zhang ¹ , Zhangting Zhao ¹ , Run Zhang ⁵ , Xinru Zhang ¹ , Wei Kang ⁹ , KaFai To ⁹ , Sachiyo Nomura ¹⁰ , Fenghua Guo ¹¹ , Shi Jiao ⁵ , Yixuan Xie ⁷ , Zhaocai Zhou ¹² ¹³ ¹⁴ , Chao Dong ¹⁵ , Hui Li ¹⁶ , Liwei An ¹⁷ ¹⁸ ¹⁹

Affiliations

1. Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University Cancer Center, School of Medicine, Tongji University, Shanghai, China.
2. School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, China.
3. Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China.
4. School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
5. State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
6. Institutes of Biomedical Sciences, Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China.
7. NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
8. Shanghai Bioprofile Technolgy Co. Ltd, Shanghai, China.
9. Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, State Key Laboratory of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
10. Department of Gastrointestinal surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
11. Department of General Surgery, Huashan Hospital, Fudan University Shanghai Medical College, Shanghai, China.
12. State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
13. Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China. [email protected].
14. Tianfu Jincheng Laboratory, Chengdu, Sichuan, China. [email protected].
15. Department of Medical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China. [email protected].
16. Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, China. [email protected].
17. Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University Cancer Center, School of Medicine, Tongji University, Shanghai, China. [email protected].
18. School of Medicine, Anhui University of Science and Technology, Huainan, Anhui, China. [email protected].
19. School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China. [email protected].
# Contributed equally.

Abstract

Protein monoaminylation represents a new layer of neural-cancer regulation, but its role in gastric tumorigenesis is not understood. Using untargeted plasma metabolomics, we revealed that the level of serotonin (5-HT) is significantly elevated in gastric Cancer (GC) patients. Functionally, 5-HT treatment dramatically promoted GC cell proliferation and tumor growth in a dose-dependent manner. Importantly, this oncogenic effect was abrogated by the inhibition of Transglutaminase 2 (TGM2), indicating a crucial role for protein serotonylation via a receptor-independent mechanism. Using a 5-HT-based chemoproteomic probe, we identified a broad spectrum of serotonylation targets, including key ferroptosis-related proteins such as Glutathione Peroxidase 4 (GPX4). Specifically, we found that GPX4 is serotonylated by TGM2 at residues Gln55 and Gln77, which increases GPX4 protein stability by attenuating its ubiquitin-mediated degradation, thereby conferring resistance to Ferroptosis and facilitating tumor growth. Clinically, TGM2 levels were positively correlated with tumoral GPX4 expression in GC patient specimens. Collectively, our results establish TGM2-mediated GPX4 serotonylation as a key mechanism driving GC progression through Ferroptosis resistance, highlighting its potential as both a diagnostic biomarker and a therapeutic target within the neural-tumor axis.