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

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.

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Publication Details

Journal
Cell Discovery
Published
2026-04-28
DOI
https://doi.org/10.1038/s41421-026-00885-6
Primary Topic
Ferroptosis and cancer prognosis
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Chunxiao Zhu, Luyang Tian, Zhaocai Zhou, Run Zhang et al.
Cell Discovery
Ferroptosis and cancer prognosis
article

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

Chunxiao Zhu, Luyang Tian, Zhaocai Zhou, Run Zhang, Sachiyo Nomura, Kang Wei, Xinwen Chen, S T Zhang, Yixuan Xie, Xinru Zhang, Fenghua Guo, Dandan Geng, X L Wang, Meng Du, Junping Bai, Liwei An, K F To, Y J Tang, H Li, Chao Dong, Zhangting Zhao, Yi Han, Shi Jiao, Zhao Jin, Wanting Li, Weisheng Hu
article en

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.

Cell DiscoveryVol. 12(1)
Tongji University (CN), China Pharmaceutical University (CN), Chinese University of Hong Kong (HK), Anhui University of Science and Technology (CN), Fudan University (CN), Kunming Medical University (CN), Inner Mongolia University (CN), Tianjin Medical University Cancer Institute and Hospital (CN), Sichuan Provincial Architectural Design and Research Institute (China) (CN), Shanghai Industrial Boiler Research Institute (China) (CN), University of Tokyo Hospital (JP), Ministry of Education (KR), Prince of Wales Hospital (CN), First Affiliated Hospital of Kunming Medical University (CN), Shanghai Tenth People's Hospital (CN), Huashan Hospital (CN), The University of Tokyo (JP)
National Natural Science Foundation of China, Fudan University, Science and Technology Commission of Shanghai Municipality, Kunming Medical University
Good health and well-being
Openalex Percentile: Top 11%
Ferroptosis and cancer prognosis
DOIOpen Access PDFOpenAlex
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