Multi-Omics Landscape of Circadian Clock Dysregulation Across the Chronic Liver Disease Spectrum.
Level 5 - mechanism / opinion, no new human data
Narrative review synthesizing mechanistic and multi-omics literature without primary human trial data
PubMed 42196548 · doi:10.3390/ijms27104571
What was done
This narrative review synthesized multi-omics literature (transcriptomics, proteomics, post-translational modification profiling, and metabolomics) examining circadian clock dysregulation across six chronic liver disease categories: metabolic dysfunction-associated fatty liver disease (MAFLD), alcoholic liver disease (ALD), viral hepatitis, hepatocellular carcinoma (HCC), liver fibrosis, and cholestatic liver disease.
What was found
Approximately half of rhythmically abundant hepatic proteins lack corresponding rhythmic mRNAs, and roughly 25% of hepatic phosphosites oscillate with a 24-hour period. Across liver pathologies, four recurring molecular motifs were identified: functional downregulation of BMAL1, attenuation of REV-ERBα oscillatory output, reduced NAD+ oscillatory amplitude, and circadian desynchronization across the gut-liver axis. Specific multi-omics findings include oncogenic kinase-driven CLOCK post-translational modifications in HCC, phosphoproteomic remodeling in MAFLD, and epigenomic clock disruption persisting following HCV clearance.
Why it matters
It highlights that transcriptomics alone misses major post-transcriptional circadian disruptions in liver disease, establishing an inferential multi-omics framework for hepatic circadian failure.
Limits
The paper is a non-systematic narrative review. It provides no primary patient data, and the authors explicitly note that a near-complete lack of temporally resolved human tissue datasets severely limits the clinical translation and actionability of these findings.
Cited by
- context Between 10% and 15% of the human protein-coding genome is regulated by circadian clocks, and 40% to 50% of those genes are involved in metabolism.