Wittke Celine I, Cheung Eric C, Athineos Dimitris, Clements Nicola, Butler Liam, Hughes Mark, Morrison Vivienne, Watt Dale M, Blyth Karen, Vousden Karen H, Humpton Timothy J
Glasgow Caledonian University, Glasgow, G4 0BA, United Kingdom.
School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, United Kingdom.
JHEP Rep. 2025 Mar 20;7(7):101397. doi: 10.1016/j.jhepr.2025.101397. eCollection 2025 Jul.
BACKGROUND & AIMS: 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.
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 obesogenic system utilising western blotting and flow cytometry. Human relevance is examined through transcriptomic analyses of patients with MASH.
Using a p53 reporter mouse, we report early and sustained activation of hepatic p53 in response to a high-fat and high-sugar diet (0.05 at 100 days in males, 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 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) and . We show that loss of TIGAR exacerbates lipid peroxidation during MASH development (0.001) and that TIGAR is engaged in human MASH (0.001).
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.
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.
p53是一种强大的肿瘤抑制因子，可协调多种应激反应程序，范围从促生存活动到细胞死亡。p53也参与组织损伤和修复过程，包括在肝脏内。代谢功能障碍相关脂肪性肝炎（MASH）是肝细胞癌的主要驱动因素，但我们对MASH分子决定因素的理解仍不完整。在此，我们研究p53在整个MASH发展过程中的活性，这对疾病预防具有重要意义。
本研究在饮食诱导和基因诱导的MASH小鼠模型背景下，利用p53活性的非侵入性成像和肝脏特异性p53缺失。采用组织病理学分析来监测疾病的不同进展。利用蛋白质印迹法和流式细胞术在致肥胖系统中评估分子机制。通过对MASH患者的转录组分析来检验与人类的相关性。
使用p53报告基因小鼠，我们发现在高脂高糖饮食后，肝脏p53出现早期且持续的激活（雄性100天时为0.05，雌性200天时为0.001）。肝脏特异性p53缺失会加速良性脂肪性肝病向MASH的进展，其特征为高水平的活性氧、广泛的纤维化和慢性炎症（每组高脂高糖组均为0.0001，n = 13）。我们的研究结果表明，p53诱导抗氧化基因p53诱导的糖酵解和凋亡调节因子（TIGAR）以及[此处原文缺失部分内容]。我们发现TIGAR缺失会在MASH发展过程中加剧脂质过氧化（0.001），并且TIGAR参与人类MASH（0.001）。
我们的工作证明了p53 - TIGAR轴在预防MASH中起重要作用，并表明氧化还原控制是防止疾病进展的一个可治疗靶向的屏障。
p53作为一种强大的肿瘤抑制因子备受关注，针对该途径的化合物已被开发并作为抗癌疗法进行试验。我们的研究结果表明，p53的早期激活同样对代谢功能障碍相关脂肪性肝炎具有保护作用，并且氧化还原控制是这种保护作用的重要介导因素。进一步研究评估在肝脏中主动激活p53以预防代谢功能障碍相关脂肪性肝炎的疗效，或给予靶向抗氧化剂以增强p53的氧化还原保护作用，可能为这种获批治疗方法较少的疾病提供新的治疗途径。
