ArticleJournal of hepatology2024
Circadian dysfunction induces NAFLD-related human liver cancer in a mouse model.
Article in Journal of hepatology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.
- Rodent model of metabolic dysfunction-associated fatty liver disease: a systematic review.Journal of gastroenterology and hepatology · 2025Pooled it
- Remodeling of the hepatic circadian transcriptome across the estrous cycle.bioRxiv : the preprint server for biology · 2026Article
- Molecular mechanisms and pathogenesis of MASH.Nature · 2026Review
- HFpEF and MASLD: converging mechanisms and clinical implications.Nature reviews. Cardiology · 2026Review
- The circadian architecture of tumor immunity: mechanistic insights and treatment strategies.Biomarker research · 2026Review
- Transcriptomic Profiling Reveals Inflammatory, Fibrotic, and Apoptotic Signatures in a Methionine-Choline-Deficient Diet-Induced Murine Model of Metabolism-Dysfunction-Associated Steatohepatitis.International journal of molecular sciences · 2026Article
- Noncanonical clock regulators control stress responses in digestive diseases.Trends in endocrinology and metabolism: TEM · 2026Review
- Network Toxicology Reveals the Mechanisms of the Plasticizer Metabolite MECPP in Metabolic Diseases.International journal of molecular sciences · 2026Article
- Rhythms of risk: the intersection of clocks, cancer, and chronotherapy.The Journal of clinical investigation · 2026Review
- Modeling the dynamics of hepatic metabolism: the predominance of 12-hour rhythmicity in metabolic adaptation.Cellular and molecular life sciences : CMLS · 2026Article
- Hepatocellular Carcinoma Around the Clock.Current oncology (Toronto, Ont.) · 2026Review
- Circadian clock genes: Their influence on liver metabolism, disease development and treatment (Review).Molecular medicine reports · 2026Review
- Neural regulation of tumor progression: implications for hepatocellular carcinoma.Frontiers in immunology · 2026Review
- Bioinformatics Analysis of the PSD Gene Family: Metastasis and Prognosis in HCC.Bioinformatics and biology insights · 2026Article
- Giant Atypical Hepatocellular Adenoma of Unknown Etiology in a Young Male: A Case Report.Journal of hepatocellular carcinoma · 2026Article
- Mitochondrial dysfunction in sepsis-induced liver injury: from pathophysiology to preclinical therapeutic targets.Journal of translational medicine · 2025Review
- Association of circadian-metabolic syndrome with incident chronic liver disease in middle-aged and elderly Chinese adults: a prospective cohort study on mediation by cardiovascular disease.European journal of medical research · 2025Article
- Metabolic and hepatic effects of semaglutide and empagliflozin on metabolic dysfunction-associated steatotic liver disease mice.World journal of hepatology · 2025Article
- Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism.Cell metabolism · 2025Article
- Melatonin, ROR-α and circadian rhythm in liver.Human cell · 2025Review
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsChronic circadian dysfunction increases the risk of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC), but the underlying mechanisms and direct relevance to human HCC have not been established. In this study, we aimed to determine whether chronic circadian dysregulation can drive NAFLD-related carcinogenesis from human hepatocytes and human HCC progression.
methodsChronic jet lag of mice with humanized livers induces spontaneous NAFLD-related HCCs from human hepatocytes. The clinical relevance of this model was analysed by biomarker, pathological/histological, genetic, RNA sequencing, metabolomic, and integrated bioinformatic analyses.
resultsCircadian dysfunction induces glucose intolerance, NAFLD-associated human HCCs, and human HCC metastasis independent of diet in a humanized mouse model. The deregulated transcriptomes in necrotic-inflammatory humanized livers and HCCs bear a striking resemblance to those of human non-alcoholic steatohepatitis (NASH), cirrhosis, and HCC. Stable circadian entrainment of hosts rhythmically paces NASH and HCC transcriptomes to decrease HCC incidence and prevent HCC metastasis. Circadian disruption directly reprogrammes NASH and HCC transcriptomes to drive a rapid progression from hepatocarcinogenesis to HCC metastasis. Human hepatocyte and tumour transcripts are clearly distinguishable from mouse transcripts in non-parenchymal cells and tumour stroma, and display dynamic changes in metabolism, inflammation, angiogenesis, and oncogenic signalling in NASH, progressing to hepatocyte malignant transformation and immunosuppressive tumour stroma in HCCs. Metabolomic analysis defines specific bile acids as prognostic biomarkers that change dynamically during hepatocarcinogenesis and in response to circadian disruption at all disease stages.
conclusionChronic circadian dysfunction is independently carcinogenic to human hepatocytes. Mice with humanized livers provide a powerful preclinical model for studying the impact of the necrotic-inflammatory liver environment and neuroendocrine circadian dysfunction on hepatocarcinogenesis and anti-HCC therapy. IMPACT AND IMPLICATIONS: Human epidemiological studies have linked chronic circadian dysfunction to increased hepatocellular carcinoma (HCC) risk, but direct evidence that circadian dysfunction is a human carcinogen has not been established. Here we show that circadian dysfunction induces non-alcoholic steatohepatitis (NASH)-related carcinogenesis from human hepatocytes in a murine humanized liver model, following the same molecular and pathologic pathways observed in human patients. The gene expression signatures of humanized HCC transcriptomes from circadian-disrupted mice closely match those of human HCC with the poorest prognostic outcomes, while those from stably circadian entrained mice match those from human HCC with the best prognostic outcomes. Our studies establish a new model for defining the mechanism of NASH-related HCC and highlight the importance of circadian biology in HCC prevention and treatment.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.