This study explores the role of the hepatic circadian clock (CC) in liver disease and hepatocellular carcinoma (HCC) development, focusing on chronic hepatitis C virus (HCV) infection. Using a human liver chimeric mouse (HLCM) model, the researchers mapped the diurnal transcriptome of human hepatocytes, revealing rhythmic expression of genes involved in metabolism, immune responses, and cell cycle regulation. HCV infection disrupted the rhythmicity of these genes and pathways, contributing to chronic liver disease and cancer. Perturbations were linked to dysregulated metabolic and oncogenic pathways, such as fatty acid metabolism, fibrosis, and MYC signaling, which are associated with liver disease progression and HCC risk.

Additionally, the study identified alterations in epigenetic regulation, particularly in histone acetylation patterns, which impacted gene expression. These changes were correlated with the disruption of key liver disease pathways. The researchers also identified rhythmic gene expression patterns linked to liver disease severity and cancer risk, which could serve as biomarkers for HCC. While the HLCM model has limitations in fully replicating virus-host interactions in humans, the findings suggest that circadian clock modulation may be a promising therapeutic target for liver disease and cancer prevention.

Reference: Mukherji A, Jühling F, Simanjuntak Y, et al. An atlas of the human liver diurnal transcriptome and its perturbation by hepatitis C virus infection. Nat Commun. 2024 Aug 29;15(1):7486. doi: 10.1038/s41467-024-51698-8. PMID: 39209804; PMCID: PMC11362569.