2. Academic Validation
  3. Extracellular Vesicle-Mediated O-GlcNAcase Transfer Drives Neuronal Necroptosis to Facilitate Gallbladder Cancer Perineural Invasion

Extracellular Vesicle-Mediated O-GlcNAcase Transfer Drives Neuronal Necroptosis to Facilitate Gallbladder Cancer Perineural Invasion

  • Cancer Res. 2025 Dec 29. doi: 10.1158/0008-5472.CAN-25-2237.
Jing-Wei Zhao 1,  Jia Yun Zhu 2,  Ziyi Yang 1,  Yang-Yang Zhai 2,  Cheng Zhao 2,  Zhichao Lu 3,  Danyang Shen 4,  Qiu-Yi Tang 2,  Xiaoling Song 2,  Lin Jiang 5,  Wen-Ting Dai 5,  Ya-Xuan Wang 6,  Yidi Zhu 2,  Liu-Qing Shi 1,  Runfa Bao 2,  Zhimin Geng 7,  Ziheng Wang 8,  Shi-Lei Liu 1,  Wei Gong 2
Affiliations

Affiliations

  • 1 XinHua Hospital Shanghai China.
  • 2 Shanghai Jiao Tong University Shanghai China.
  • 3 Affiliated Hospital of Nantong University China.
  • 4 First Affiliated Hospital of Soochow University Suzhou, Jiangsu China.
  • 5 Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China.
  • 6 First Affiliated Hospital of Harbin Medical University Harbin China.
  • 7 First Affiliated Hospital of Xi'an Jiaotong University Xi'an, Shanxi China.
  • 8 University of Macau China.
PMID: 41460724 DOI: 10.1158/0008-5472.CAN-25-2237
Abstract

Peripheral nerve invasion (PNI) is an early and decisive step in gallbladder Cancer (GBC) progression that strongly predicts poor post-surgical outcome. The tumor-neuron interactions that drive PNI could represent potential targets and biomarkers to improve treatment of GBC. Here, we demonstrated that GBC provoked Necroptosis of neurons to enable PNI. GBC cells transferred extracellular vesicles (EVs) containing O-GlcNAcase (OGA) to neurons, which activated RIPK1-dependent Necroptosis. Mechanistically, EV-derived OGA suppressed RIPK1 glycosylation while enhancing its phosphorylation, thereby activating the RIPK1/RIPK3/MLKL axis to trigger neuronal Necroptosis. Subsequent neuronal release of HMGB1 engaged RAGE on GBC cells, establishing a loop that accelerated PNI. Moreover, the RAGE antagonist FPS-ZM1 synergized with gemcitabine to suppress tumor progression. Collectively, these findings uncover an EV-mediated crosstalk between GBC cells and neurons in which RIPK1-dependent Necroptosis and its effector HMGB1 drive PNI, positioning the HMGB1-RAGE axis as a tractable therapeutic target.

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