AFB1 consolidates HBV harm to induce liver injury and carcinogenic risk by inactivating FTCD-AS1-PXR-MASP1 axis.

Abstract

Aflatoxin B1 (AFB1) has been reported to synergize with hepatitis B virus (HBV) to induce development of hepatocellular carcinoma (HCC). Precise daily exposure to AFB1 and its contribution to liver injury have not been quantified and have even been disregarded due to lack of convenient detection, and the strong species specificity of HBV infection has restricted research on their synergistic harm. Hence, our objective was to investigate the molecular mechanisms by which AFB1 exacerbates HBV-related injury. We constructed tree shrew models with 400 μg HBV plasmid and 4 mg/kg AFB1 co-exposure for 4-6 days. Injury and molecule expression resulting from HBV and AFB1 toxicity were observed in vivo and in vitro. Expression datasets of tree shrew livers, human HCC, and pregnane X receptor (PXR) activation were employed to screen vital pathways and target genes. The oncogenic hepatitis B virus x (HBx) protein, HBV-related histopathological damage, metabolic dysregulation, and several cancer-related signaling pathways were enriched in injured tree shrew livers, and PXR signaling was inhibited after co-exposure to HBV and AFB1. Furthermore, in human HCC and HBV-integrated Hep3B and HepG2.215 cells, FTCD Antisense RNA 1 (FTCD-AS1), PXR and mannose-binding lectin-associated serine protease 1 (MASP1) exhibited strong correlation. Overexpression of FTCD-AS1 and PXR alleviated cell damage in exposure to 5 μM AFB1 for 48 h. In summary, inactivation of the FTCD-AS1-PXR-MASP1 axis was pinpointed as the key event in AFB1-enhanced HBV infection, metabolic dysregulation and carcinogenic injury.