This study investigates how hepatocellular p53 activity and dietary cholesterol influence fibrosis during metabolic dysfunction-associated steatohepatitis (MASH). The authors address both local hepatic disease and systemic fibrotic consequences in distal organs, given that liver fibrosis is a major determinant of hepatocellular carcinoma risk and contributes to dysfunction in organs such as the kidneys, lungs, and heart.
Multiple complementary approaches were used. An inducible genetic mouse model that stabilises p53 through loss of the MDM2 E3 ubiquitin ligase was employed to test the effects of heightened hepatocellular p53. Diet-induced MASH models with different cholesterol compositions were used to assess the role of dietary cholesterol. In vitro, an obesogenic system and a human multicomponent LiverACE spheroid model were used to probe cellular responses to steatotic stress. Non-invasive imaging and histopathology assessed p53 activity, MASH severity, and multiorgan fibrosis in vivo. Cytokine arrays and analyses of human MASH transcriptomic and proteomic datasets complemented in vivo and in vitro findings to probe molecular drivers and patient relevance.
Using the inducible mouse model of MDM2 E3 ubiquitin ligase deficiency, stabilisation of hepatocellular p53 produced progressive fibrotic damage in the liver and strong hepatocellular expression of the p53 transcriptional target CDKN1A/p21 (referred to as p21). Notably, this genetic perturbation also induced p21 expression and fibrotic changes in the kidneys of male mice, demonstrating a sex-specific systemic effect linked to hepatic p53 stabilisation.
In diet-induced MASH models, the authors observed that development of liver fibrosis depended on both cholesterol and p53. Diets containing cholesterol promoted hepatic fibrosis with high hepatocellular p21 expression. Mirroring the genetic model, male mice with diet-induced MASH developed induction of p21 and fibrosis in the kidneys; fibrosis was also detected in the lungs and heart of male MASH mice. These findings link dietary cholesterol and hepatic p53 activity to a male-specific multiorgan fibrotic phenotype in MASH.
Interventions that removed dietary cholesterol or selectively abolished p53 in the liver blunted hepatic fibrosis and prevented systemic induction of p21 and fibrosis. A cholesterol-free obesogenic diet and liver-specific loss of p53 each mitigated both local liver fibrosis and systemic fibrotic signalling, supporting a model in which hepatic p53 and dietary cholesterol act together to drive pro-fibrotic responses.
Mechanistically, the investigators report that p53 activity in the liver induces expression of senescence-associated secretory phenotype (SASP) factors. Among these, GDF15 was highlighted as a p53-induced SASP factor in vivo. These senescence-associated secreted factors provide a plausible link between hepatocellular stress and distal organ effects through circulating mediators.
A human multicomponent LiverACE spheroid model exposed to steatotic stress showed a concordant trend toward increased GDF15 protein abundance, supporting translational relevance of the mouse mechanistic findings. Analyses of human MASH datasets identified elevated circulating GDF15 in advanced disease. In humans, higher circulating GDF15 levels correlated with increased TNFRSF1A and EPHA2—markers that have been linked to kidney injury—suggesting potential biomarkers that might identify patients at risk of multiorgan fibrosis in MASH.
The work positions undue hepatic p53 activity and dietary cholesterol as drivers of multiorgan fibrosis in MASH, with effects that were sex-specific in mice, affecting males but not females. These findings suggest that hepatic senescence and SASP factor release—including GDF15—could mediate systemic fibrotic responses and that circulating markers may help identify at-risk patients.
The source summary does not report quantitative effect sizes, detailed sample sizes, precise statistical outcomes, or specific timelines for fibrosis development. Further studies would be needed to define causal pathways in humans, determine whether the sex specificity observed in mice applies to patients, and validate circulating markers such as GDF15, TNFRSF1A, and EPHA2 as predictors of multiorgan fibrosis in clinical cohorts.