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

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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 gene TP53-induced glycolysis and apoptosis regulator (TIGAR) in vivo and in vitro . We show that loss of TIGAR exacerbates lipid peroxidation during MASH development in vivo ( p < 0.001) and that TIGAR is engaged in human MASH ( p < 0.001). Conclusions Our work demonstrates an important role for the p53-TIGAR axis in protecting against MASH and implicates redox control as a barrier against disease progression that is therapeutically targetable. Impact and implications p53 is of intense interest as a potent tumour suppressor and compounds targeting the pathway have been developed and trialled as anti-cancer therapies. Our findings suggest that early activation of p53 is similarly protective against metabolic dysfunction-associated steatohepatitis and that redox control is an important mediator of this protection. Further studies evaluating the efficacy of proactive activation of p53 in the liver to prevent metabolic dysfunction-associated steatohepatitis, or administration of targeted antioxidants to augment p53 redox protection, could provide new treatment approaches for a condition with few approved therapies.

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