Metabolomics reveals ascorbic acid inhibits ferroptosis in hepatocytes and boosts the effectiveness of anti-PD1 immunotherapy in hepatocellular carcinoma

  • Cancer Cell Int. 2024 May 31;24(1):192. doi: 10.1186/s12935-024-03342-0.
Guoqiang Sun  #  1  2 ,  Chuan Liu  #  1 ,  Zhengqing Lu  #  1 ,  Jinyu Zhang  #  3 ,  Hengsong Cao  1 ,  Tian Huang  1 ,  Mingrui Dai  4 ,  Hanyuan Liu  2 ,  Tingting Feng  5 ,  Weiwei Tang  6 ,  Yongxiang Xia  7
Affiliations
  • 1. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, China.
  • 2. Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 3. Central Laboratory, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 4. Stomatological college of Nanjing Medical University, Nanjing, China.
  • 5. Central Laboratory, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. [email protected].
  • 6. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, China. [email protected].
  • 7. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary cancers, Nanjing, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 38822322 DOI: 10.1186/s12935-024-03342-0
Abstract

Background: Immunotherapy combined with molecular targeted therapy is increasingly popular in patients with advanced hepatocellular carcinoma (HCC). However, immune-related adverse events(irAEs) brought on by immunotherapy increase the likelihood of side effects, thus it is important to look into ways to address this issue.

Methods: Different metabolite patterns were established by analyzing metabolomics data in liver tissue samples from 10 patients(divided into severe and mild liver injury) before and after immuno-targeted therapy. After establishing a subcutaneous tumor model of HCC, the mice were divided into PBS group, ascorbic acid(AA) group, and anti-PD1 + tyrosine kinase inhibitor (TKI) group, anti-PD1 + TKI + AA group. Liver tissue were stained with hematoxylin-eosin staining(HE) and the content of aspartate transaminase (AST) and alanine transaminase(ALT) in blood were determined. The mechanism was confirmed by western blotting, mass cytometry, and Other techniques.

Results: Through metabolomics analysis, AA was significantly reduced in the sample of patients with severe liver injury caused by immuno-targeted therapy compared to patients with mild liver injury. The addition of AA in vivo experiments demonstrated a reduction in liver injury in mice. In the liver tissues of the anti-PD1 + TKI + AA group, the protein expressions of SLC7A11,GPX4 and the level of glutathione(GSH) were found to be higher compared to the anti-PD1 + TKI group. Mass cytometry analysis revealed a significant increase in the CD11b+CD44+ PD-L1+ cell population in the AA group when compared to the PBS group.

Conclusions: AA could reduce liver injury by preventing hepatocyte SLC7A11/GPX4 Ferroptosis and improve the immunotherapy effect of anti-PD1 by boosting CD11b+CD44+PD-L1+cell population in HCC.

Keywords
Anti-PD1; Ascorbic acid; Ferroptosis; Hepatocellular carcinoma; Liver injury; Metabolomics analysis.
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