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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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  • Junping Bai,
  • Dandan Geng,
  • Xinwen Chen,
  • Wanting Li,
  • Xiaowei Wang,
  • Luyang Tian,
  • Yi Han,
  • Zhao Jin,
  • Meihang Du,
  • Yang Tang,
  • Weisheng Hu,
  • Chunxiao Zhu,
  • Shan Zhang,
  • Zhangting Zhao,
  • Run Zhang,
  • Xinru Zhang,
  • Wei Kang,
  • KaFai To,
  • Sachiyo Nomura,
  • Fenghua Guo,
  • Shi Jiao,
  • Yixuan Xie,
  • Zhaocai Zhou,
  • Chao Dong,
  • Hui Li,
  • Liwei An

摘要

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.