2. Academic Validation
  3. MVP-LCN2 axis triggers evasion of ferroptosis to drive hepatocarcinogenesis and sorafenib resistance

MVP-LCN2 axis triggers evasion of ferroptosis to drive hepatocarcinogenesis and sorafenib resistance

  • Drug Resist Updat. 2025 Jul:81:101246. doi: 10.1016/j.drup.2025.101246.
Jiawen Xu 1,  Bo Wang 2,  Qiaoyu Liu 2,  Sheng Guo 3,  Chen Chen 2,  Jun Wu 4,  Xiaoya Zhao 1,  Mengmeng Li 1,  Zhuang Ma 1,  Shimeng Zhou 1,  Yun Qian 1,  Yijin Huang 5,  Zhangding Wang 2,  Chuanjun Shu 6,  Qingxiang Xu 7,  Jingjing Ben 8,  Qiang Wang 9,  Shouyu Wang 10
Affiliations

Affiliations

  • 1 Nanjing University Medical School, Nanjing, China.
  • 2 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor Immunotherapy; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, China.
  • 3 Crown Bioscience Inc, Suzhou, China.
  • 4 Medical College, Yangzhou University, Yangzhou, China.
  • 5 School of Medicine, University of Missouri, Columbia, USA.
  • 6 Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China.
  • 7 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor Immunotherapy; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, China. Electronic address: xqx2016nj@sina.com.
  • 8 Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China. Electronic address: bjj@njmu.edu.cn.
  • 9 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor Immunotherapy; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, China. Electronic address: wangqiang@ahmu.edu.cn.
  • 10 Nanjing University Medical School, Nanjing, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor Immunotherapy; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, China; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. Electronic address: sywang@nju.edu.cn.
PMID: 40262414 DOI: 10.1016/j.drup.2025.101246
Abstract

RNA-binding proteins (RBPs) are critical regulators in tumorigenesis and therapy resistance by modulating RNA metabolism. However, the role of RBPs in hepatocarcinogenesis and progression remains elusive. Here, RBPs screening and integrating analyses identify major vault protein (MVP) as an oncogenic RBP in the occurrence of hepatocellular carcinoma (HCC) and sorafenib resistance via suppressing Ferroptosis. Mechanistically, Reactive Oxygen Species (ROS) induces STAT3-mediated MVP transcription activation and high expression in HCC cells. Subsequently, phosphoglycerate mutase family member 5 (PGAM5) directly dephosphorylates MVP at S873, facilitating its binding to the mRNA of iron-sequestering cytokine LCN2 and maintains its stability, thereby attenuating Ferroptosis by reducing lipid peroxidation and intracellular Fe2+ content following sorafenib treatment. Notably, tenapanor, a potent pharmacological inhibitor of MVP, effectively disrupts the interaction between MVP and LCN2 mRNA and enhances Ferroptosis and sorafenib sensitivity. Collectively, these findings underscore the central role of MVP in hepatocarcinogenesis and offer promising avenues to improve HCC treatment.

Keywords

Ferroptosis; Hepatocellular carcinoma; MVP; RNA-binding protein; Sorafenib resistance.

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