p53 and TIGAR promote redox control to protect against metabolic dysfunction-associated steatohepatitis

作者：Celine I Wittke, Eric C. Cheung, Dimitris Athineos, Nicola Clements, Liam Butler, Mark Hughes, Vivienne Morrison, Dale M. Watt, Karen Blyth, Karen H. Vousden, Timothy J. Humpton · 发表于：JHEP Reports · 年份：2025 · DOI：10.1016/j.jhepr.2025.101397 · 被引用次数：6 · 研究领域：Liver Disease Diagnosis and Treatment、Cancer, Hypoxia, and Metabolism、Cancer, Lipids, and Metabolism

Background & Aims TP53 is a potent tumour suppressor that coordinates diverse stress response programmes, ranging from pro-survival activities to cell death. p53 is also engaged during tissue damage and repair, including within the liver. Metabolic dysfunction-associated steatohepatitis (MASH) is a major driver of hepatocellular carcinoma, but our understanding of the molecular determinants of MASH remains incomplete. Here, we investigate p53 activity throughout MASH development, with implications for disease prevention. Methods This study utilises non-invasive imaging of p53 activity and liver-specific p53 deletion within the context of mouse models of diet and genetically induced MASH. Histopathological analyses are employed to monitor differential disease progression. Molecular mechanisms are assessed within an in vitro obesogenic system utilising western blotting and flow cytometry. Human relevance is examined through transcriptomic analyses of patients with MASH. Results Using a p53 reporter mouse, we report early and sustained activation of hepatic p53 in response to a high-fat and high-sugar diet ( p < 0.05 at 100 days in males, p < 0.001 at 200 days in females). Liver-specific loss of p53 accelerates progression of benign fatty liver disease to MASH, which is characterised by high levels of reactive oxygen species, extensive fibrosis, and chronic inflammation (all p < 0.0001, n=13 per high-fat high-sugar group). Our findings indicate that p53 induces the antioxidant g...