2. Academic Validation
  3. GSTA1/CTNNB1 axis facilitates sorafenib resistance via suppressing ferroptosis in hepatocellular carcinoma

GSTA1/CTNNB1 axis facilitates sorafenib resistance via suppressing ferroptosis in hepatocellular carcinoma

  • Pharmacol Res. 2024 Dec:210:107490. doi: 10.1016/j.phrs.2024.107490.
Shiwen Ma 1,  Fei Xie 2,  Xiaohu Wen 1,  Yao Mawulikplimi Adzavon 2,  Ruping Zhao 2,  Jinyi Zhao 2,  Han Li 2,  Yanqi Li 2,  Jingtao Liu 3,  Chen Liu 4,  Yang Yi 2,  Pengxiang Zhao 2,  Boqing Wang 5,  Wei Zhao 6,  Xuemei Ma 7
Affiliations

Affiliations

  • 1 College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China; Key Laboratory of Carcinogenesis and Translational Research/Ministry of Education, Department of Clinical laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, China.
  • 2 College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China.
  • 3 Key Laboratory of Carcinogenesis and Translational Research/Ministry of Education, Department of Clinical laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, China.
  • 4 Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China.
  • 5 Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China. Electronic address: bqwanghps@163.com.
  • 6 Key Laboratory of Carcinogenesis and Translational Research/Ministry of Education, Department of Clinical laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, China. Electronic address: weizhao@bjcancer.org.cn.
  • 7 College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Beijing Molecular Hydrogen Research Center, Beijing 100124, China. Electronic address: xmma@bjut.edu.cn.
PMID: 39510148 DOI: 10.1016/j.phrs.2024.107490
Abstract

The emergence of sorafenib resistance has become a predominant impediment and formidable dilemma in the therapeutic approach for hepatocellular carcinoma (HCC). Although the approval of next-generation drugs as alternatives to sorafenib is a significant development, the concurrent use of inhibitors that target additional key molecular pathways remains an effective strategy to mitigate the acquisition of resistance. Here, we identified Glutathione S-transferase Alpha 1 (GSTA1) as a critical modulator of sorafenib resistance (SR) in hepatocellular carcinoma (HCC) based on our findings from experiments conducted on recurrent liver Cancer tissues, xenograft mouse models, organoids, and sorafenib-resistant cells. Elevated GSTA1 levels are strongly associated with adverse clinical prognoses. The knockout of GSTA1 reinstates sorafenib sensitivity, whereas its overexpression attenuates drug efficacy. Mechanistically, GSTA1 enhances the accumulation of lipid peroxides and suppresses Ferroptosis by exerting its peroxidase function to regulate the SR. Notably, the upregulation of GSTA1 expression is mediated by the transcription factor CTNNB1 (β-catenin), resulting in the formation of a cytoplasmic complex between GSTA1 and CTNNB1. This complex facilitates the nuclear translocation of CTNNB1, establishing a positive feedback loop. The combined use of GSTA1 and CTNNB1 inhibitors demonstrated synergistic anti-tumour effects through the induction of Ferroptosis both in vitro and in vivo. Our findings reveal a novel regulatory role of the GSTA1/CTNNB1 axis in Ferroptosis, suggesting that targeting GSTA1 and CTNNB1 could be a promising strategy to circumvent sorafenib resistance in HCC.

Keywords

Drug resistance; Ferroptosis; GSTA1; Hepatocellular carcinoma (HCC); Sorafenib.

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