2. Academic Validation
  3. HBV-induced N6 methyladenosine modification of PARP1 enhanced AFB1-related DNA damage and synergistically contribute to HCC

HBV-induced N6 methyladenosine modification of PARP1 enhanced AFB1-related DNA damage and synergistically contribute to HCC

  • Ecotoxicol Environ Saf. 2025 Jun 15:298:118254. doi: 10.1016/j.ecoenv.2025.118254.
Xin Zhou 1,  Tianman Li 2,  Haixiang Xie 3,  Huasheng Huang 3,  Kejian Yang 3,  Xiaoyun Zeng 4,  Tao Peng 5
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, PR China; Guangxi Medical University, Nanning 530021, PR China; Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer (Guangxi Medical University), Nanning 530021, PR China; Key Laboratory of early Prevention & Treatment for regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi 530021, PR China; Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, PR China. Electronic address: zhouxin_gxmu@163.com.
  • 2 Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital of Guangxi Medical University, Yulin, Guangxi 537000, PR China.
  • 3 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, PR China.
  • 4 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, PR China; Guangxi Medical University, Nanning 530021, PR China; Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, PR China. Electronic address: zengxiaoyun@gxmu.edu.cn.
  • 5 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, PR China; Guangxi Medical University, Nanning 530021, PR China; Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer (Guangxi Medical University), Nanning 530021, PR China; Key Laboratory of early Prevention & Treatment for regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi 530021, PR China. Electronic address: pengtaogmu@163.com.
PMID: 40344782 DOI: 10.1016/j.ecoenv.2025.118254
Abstract

Hepatitis B virus (HBV) Infection and Aflatoxin B1 (AFB1) exposure are major contributors to the high incidence of hepatocellular carcinoma (HCC) in Southern Africa and Southeast Asia. Investigating the synergistic mechanisms between these factors will help to elucidate the pathogenesis, identify potential therapeutic targets, and reduce disease incidence. Oxidative stress in the cell line was assessed using ROS, MDA, and 8-OHdG assays. DNA damage was evaluated through the Comet assay and γ-H2AX detection. Sanger Sequencing was employed to detect TP53 R249S mutations. RIP and Me-RIP assays were performed to investigate the interaction between YTH N6-methyladenosine RNA Binding Protein 2 (YTHDF2) and Poly(ADP-ribose) polymerase 1 (PARP1). The exogenous Cytochrome P450 3A4(CYP3A4)-Sodium/Taurocholate Cotransporting Polypeptide(NTCP) expression cell model was validated for its ability to metabolize AFB1 and support HBV Infection. HBV Infection increased YTHDF2 expression while suppressing PARP1 both in vitro and in vivo. Additionally, HBV Infection exacerbated AFB1-induced DNA damage in both experimental settings. Interference with or pharmacological inhibition of PARP1 significantly worsened HBV- and AFB1-induced DNA damage, while PARP1 overexpression partially alleviated the damage. These findings provide compelling evidence that HBV aggravates AFB1-induced DNA damage by inhibiting PARP1. Further investigation revealed that YTHDF2 interference reversed HBV's regulatory effect on PARP1, while exogenous YTHDF2 addition mimicked HBV's effect by promoting PARP1 degradation. RIP (RNA immunoprecipitation) experiments confirmed that YTHDF2 directly binds to PARP1 mRNA, and MeRIP experiments showed that YTHDF2 increases m6A methylation of PARP1 mRNA. CYP3A4-NTCP overexpression enables liver cell lines to metabolize AFB1 and support HBV Infection. HBV enhances AFB1-induced DNA damage by promoting PARP1 degradation, thereby synergistically contributing to HCC development.

Keywords

Aflatoxin; DNA damage; HCC; Hepatitis B virus; Oxidative stress.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-147886
    99.10%, PARP1 Inhibitor