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

Background & Aims: 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 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 ( 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.