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GPX3 suppresses gallbladder cancer progression by modulating redox balance, glycolysis, and anti-tumor immunity
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  • Published: 02 April 2026

GPX3 suppresses gallbladder cancer progression by modulating redox balance, glycolysis, and anti-tumor immunity

  • Zuyi Ma1,2,3,
  • Jia Sun3,
  • Xin Wu3,
  • Changzhen Shang1,2 &
  • …
  • Binglu Li  ORCID: orcid.org/0000-0002-6264-30073 

Oncogenesis , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer
  • Molecular biology

Abstract

Gallbladder cancer (GBC) is an aggressive malignancy characterized by metabolic plasticity and profound immune evasion. However, the functional role of glutathione peroxidase 3 (GPX3), a secreted antioxidant enzyme, in these processes remains unclear. Multi-omics analyses of paired GBC and adjacent non-tumor tissues revealed consistent downregulation of GPX3, which correlated with reactive oxygen species (ROS) accumulation and enhanced glycolytic activity. Functional restoration of GPX3 in GBC cells reduced intracellular ROS levels, suppressed the expression of glycolysis-related enzymes, and consequently impaired tumor proliferation, migration, and invasion. In xenograft models, GPX3 overexpression markedly attenuated tumor growth and lung metastasis. Notably, GPX3 restoration also enhanced CD8+ T cell infiltration and elevated pro-inflammatory cytokine production, suggesting reversal of tumor-associated immunosuppression. These findings identify GPX3 as a critical tumor suppressor that integrates redox regulation, metabolic reprogramming, and immune activation to restrict malignant progression. Targeting GPX3 or its downstream pathways may represent a promising therapeutic strategy to simultaneously suppress gallbladder cancer aggressiveness and reinforce anti-tumor immunity.

Data availability

The proteomics data have been deposited in public databases. The data can be accessed through the following identifiers: iProX: ID IPX0011270000. ProteomeXchange: ID PXD061486. The sequencing data have been uploaded to the NCBI database under the following identifiers: Submissions: SUB15151673. BioProject: PRJNA1231233. SRA IDs: Paracancerous group: SRR32560247, SRR32560246, SRR32560245. Tumor group: SRR32560244, SRR32560243, SRR32560242. All data are publicly available and can be accessed via the provided links.

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Funding

This study was supported by the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (GZC20251430), Beijing Bethune Charitable Foundation (GDZL040), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No.2022-I2M-C&T-A-004), National High Level Hospital Clinical Research Funding (No.2022-PUMCH-B-005), Fundamental Research Funds for the Central Universities (3332024119), Scientific Research Promotion Program for Clinical Medicine (2025CMFA08), Basic and Applied Basic Research Foundation of Guangdong Province (2023A1515220211), and Guangzhou Municipal Science and Technology Project (2024B03J1335) and Sun Yat-sen Pilot Scientific Research Fund (YXQH202608).

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Authors and Affiliations

  1. Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China

    Zuyi Ma & Changzhen Shang

  2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China

    Zuyi Ma & Changzhen Shang

  3. Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    Zuyi Ma, Jia Sun, Xin Wu & Binglu Li

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Contributions

Zuyi Ma: Conceptualization, Investigation, Formal Analysis, Writing – Original Draft. Jia Sun: Investigation, Validation, Data Curation. Xin Wu: Investigation, Methodology. Changzhen Shang: Supervision, Resources, Writing – Review & Editing, Funding Acquisition. Binglu Li: Supervision, Project Administration, Writing – Review & Editing, Funding Acquisition. All authors reviewed and approved the final manuscript.

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Correspondence to Changzhen Shang or Binglu Li.

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This study was approved by the Ethics Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Science, and Peking Union Medical College (Approval No. I-23PJ352). All procedures were performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all individual participants included in the study. The experimental procedures and animal use protocols were approved by the Institutional Animal Ethics Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Science, and Peking Union Medical College (No. I-23PJ352).

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Ma, Z., Sun, J., Wu, X. et al. GPX3 suppresses gallbladder cancer progression by modulating redox balance, glycolysis, and anti-tumor immunity. Oncogenesis (2026). https://doi.org/10.1038/s41389-026-00603-7

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  • Received: 29 August 2025

  • Revised: 13 January 2026

  • Accepted: 13 February 2026

  • Published: 02 April 2026

  • DOI: https://doi.org/10.1038/s41389-026-00603-7

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