Halting hepatocellular carcinoma: Identifying intercellular crosstalk in HBV-driven disease

Area of Science:

• Hepatology
• Oncology
• Virology

Background:

• Hepatitis B virus (HBV) infection is a major cause of liver fibrosis and hepatocellular carcinoma (HCC).
• Antiviral therapies do not prevent HCC development in all patients.
• Understanding HBV-induced cell crosstalk is crucial for managing liver disease progression.

Purpose of the Study:

• To investigate the mechanisms of HBV-induced hepatocyte-hepatic stellate cell (HSC) crosstalk.
• To determine the role of this crosstalk in liver fibrosis and HCC development.
• To identify potential therapeutic targets within this pathway.

Main Methods:

• Utilized MYC-driven liver cancer stem cell organoids, HCC-patient-derived xenograft (PDX) models, and HBV replication models.
• Analyzed HBV transcription effects on hepatocyte development, DNA repair, and glycolysis.
• Investigated the activation of nicotinamide phosphoribosyltransferase (NAMPT) via ATR and its downstream effects.

Main Results:

• HBV transcription impacted hepatocyte development, activated DNA repair, and promoted glycolysis.
• HBV activated NAMPT through ATR, initiating NAMPT-insulin receptor (INSR)-mediated crosstalk.
• This crosstalk induced HSC myofibroblast differentiation and activated telomere maintenance via PARP1 lactylation.

Conclusions:

• Inhibition of the ATR-NAMPT-INSR-PARP1 pathway effectively blocks HBV-induced liver fibrosis and HCC.
• Targeting this pathway presents a promising therapeutic strategy for chronic HBV infection.
• This study elucidates a novel mechanism driving HBV-associated liver pathology.