---
title: "Cholesterol and p53 drive senescence and multiorgan fibrosis in MASH"
id: "biorxiv-1-cholesterol-and-p53-promote-senescence-and-systemic-fibrosis-in-metabolic"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-1-cholesterol-and-p53-promote-senescence-and-systemic-fibrosis-in-metabolic"
content_type: "clinical_feed_article"
specialty: "Gastroenterology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.02.748892v1?rss=1"
published_at: "2026-09-03T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Cholesterol and p53 drive senescence and multiorgan fibrosis in MASH
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-1-cholesterol-and-p53-promote-senescence-and-systemic-fibrosis-in-metabolic
- **Specialty:** [Gastroenterology](https://medichelpline.com/clinical-feed/gastroenterology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.02.748892v1?rss=1)
- **Published At:** 2026-09-03T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- This study examines how hepatic **p53** activity and **cholesterol** influence fibrosis locally in the liver and systemically across organs during metabolic dysfunction-associated steatohepatitis (**MASH**). - Authors used an inducible mouse model that stabilises p53 via loss of the MDM2 E3 ubiquitin ligase, diet-induced MASH models with varying cholesterol content, and an in vitro obesogenic liver spheroid system to probe mechanisms. - Hepatocellular stabilisation of p53 (MDM2 E3 loss) produced progressive liver fibrosis, strong hepatocellular expression of the p53 target **CDKN1A/p21**, and induced **p21** expression and fibrosis in the kidneys of male mice, demonstrating a sex-specific effect. - Diet-induced MASH with cholesterol reproduced similar findings: cholesterol- and p53-dependent hepatic fibrosis, elevated hepatocellular **p21**, and induction of **p21** and fibrosis in male kidneys; lungs and heart also showed fibrosis in male MASH mice. - Both a cholesterol-free obesogenic diet and liver-specific loss of p53 reduced hepatic fibrosis and prevented systemic induction of **p21** and fibrosis, implicating hepatic p53 and dietary cholesterol in driving multi-organ fibrotic responses. - Mechanistic data indicate p53 promotes hepatic expression of senescence-associated secretory phenotype (SASP) factors, including **GDF15**, in vivo; human multicomponent LiverACE spheroids showed a trend to increased GDF15 protein with steatotic stress. - In human MASH datasets, circulating **GDF15** was elevated in advanced disease and correlated with markers (TNFRSF1A, EPHA2) previously linked to kidney injury, suggesting potential circulating biomarkers for at-risk patients. - The work highlights undue hepatic p53 activity as a driver of multiorgan fibrosis in a sex-specific (male) manner and implicates cholesterol as a promoter of this pro-fibrotic environment. Details such as quantitative effects, exact sample sizes, and statistical measures were not reported in the summary available.
## Clinical Analysis & Structured Key Points
Cholesterol and p53 promote senescence and systemic fibrosis in metabolic dysfunction-associated steatohepatitis | bioRxiv Skip to main content New Results Cholesterol and p53 promote senescence and systemic fibrosis in metabolic dysfunction-associated steatohepatitis View ORCID Profile Celine I Wittke , View ORCID Profile Dale M Watt , View ORCID Profile Liam Butler , View ORCID Profile Anabel Martinez Lyons , View ORCID Profile Cassie J Clarke , View ORCID Profile Clara Mullen , View ORCID Profile Nicola Clements , View ORCID Profile Amy Lawlor , View ORCID Profile Dimitris Athineos , View ORCID Profile Ashleigh Young , View ORCID Profile Douglas J Strathdee , View ORCID Profile Colin Nixon , View ORCID Profile Leonard J Nelson , View ORCID Profile Thomas G Bird , View ORCID Profile Karen H Vousden , View ORCID Profile Karen Blyth , View ORCID Profile Jennifer Crowe , View ORCID Profile Timothy J Humpton doi: https://doi.org/10.64898/2026.09.02.748892 Celine I Wittke 1 Glasgow Caledonian University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Celine I Wittke Dale M Watt 2 CRUK Scotland Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Dale M Watt Liam Butler 1 Glasgow Caledonian University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Liam Butler Anabel Martinez Lyons 3 Edinburgh Napier University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Anabel Martinez Lyons Cassie J Clarke 2 CRUK Scotland Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Cassie J Clarke Clara Mullen 2 CRUK Scotland Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Clara Mullen Nicola Clements 1 Glasgow Caledonian University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nicola Clements Amy Lawlor 2 CRUK Scotland Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Amy Lawlor Dimitris Athineos 2 CRUK Scotland Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Dimitris Athineos Ashleigh Young 2 CRUK Scotland Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Ashleigh Young Douglas J Strathdee 2 CRUK Scotland Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Douglas J Strathdee Colin Nixon 2 CRUK Scotland Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Colin Nixon Leonard J Nelson 3 Edinburgh Napier University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Leonard J Nelson Thomas G Bird 2 CRUK Scotland Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Thomas G Bird Karen H Vousden 4 The Francis Crick Insitute Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Karen H Vousden Karen Blyth 2 CRUK Scotland Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Karen Blyth Jennifer Crowe 1 Glasgow Caledonian University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jennifer Crowe Timothy J Humpton 1 Glasgow Caledonian University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Timothy J Humpton For correspondence: timothy.humpton{at}gcu.ac.uk Abstract Info/History Metrics Supplementary material Preview PDF Abstract Background & aims: TP53 (p53) coordinates diverse cellular stress response programmes including pro-survival activities, senescence, and cell death. During tissue damage, p53 can shape both the local cellular response to injury, including the fibrotic response, and influence distal organ biology. Fibrosis in the liver is a major driver of hepatocellular carcinoma (HCC) risk within metabolic dysfunction-associated steatohepatitis (MASH). It is also an important determinant of dysfunction in multiple distal tissues including the kidneys, lungs, and heart. Despite significant clinical burden, our understanding of the molecular determinants of fibrotic MASH and its relationship to multiorgan fibrosis remain incomplete. Here, we investigate local and systemic effects of hepatocellular p53 activity and cholesterol during MASH development, with implications for disease prevention. Methods: This study utilised a genetic model of stabilised p53, diet-induced MASH models with varying cholesterol compositions, and an in vitro obesogenic system to investigate p53 activity during liver disease development. Non-invasive imaging and histopathological analyses were employed to monitor p53 activity, MASH, and multiorgan fibrosis in vivo. Complementary approaches, including in vitro human multicomponent liver spheroids, cytokine arrays, and analyses of human MASH transcriptomic and proteomic datasets, were used to examine molecular drivers and patient relevance. Results: Using an inducible mouse model of MDM2 E3 ubiquitin ligase deficiency to stabilise p53, we report that hepatocellular MDM2 E3 loss results in progressive fibrotic damage, robust hepatocellular expression of the p53 target gene CDKN1A/p21 (p21),and induces p21 and fibrosis in the kidneys of male mice in a sex-specific manner. In diet-induced MASH, we observe cholesterol and p53-dependent development of liver fibrosis, high expression of hepatocellular p21, and induction of p21 and fibrosis in the kidneys of male mice-reminiscent of features observed in MDM2 E3-deficient mice. We also observe fibrosis in the lungs and heart of male MASH mice. Both a cholesterol-free obesogenic diet and liver-specific loss of p53 mitigate hepatic fibrosis and systemic induction of p21 and fibrosis. Mechanistically, p53 induces hepatic expression of senescence-associated secretory phenotype (SASP) factors, including GDF15, in vivo. A human multicomponent LiverACE spheroid model showed a concordant trend towards increased GDF15 protein abundance under steatotic stress, while in humans, elevated circulating GDF15 levels in advanced MASH correlate with increased TNFRSF1A and EPHA2, circulating markers linked to kidney injury. Conclusions: Our work identifies undue p53 activity within the liver as a driver of multiorgan fibrosis in a sex-specific manner, affecting male but not female mice. We implicate cholesterol in promoting this pro-fibrotic environment in vivo and highlight circulating factors that could identify at-risk patients for multiorgan fibrosis in MASH. Competing Interest Statement KHV is on the board of directors and shareholder of Bristol Myers Squibb and on the science advisory board (with stock options) of RAZE Therapeutics, Volastra Pharmaceuticals and Kovina Therapeutics. She is a co-founder, consultant and shareholder of Faeth Therapeutics, a company exploring the impact of non-essential amino acid restriction on therapy in patients. She is also on the advisory board of Cell, Cancer Cell, Molecular Cell, Cell Metabolism and Cell Press Blue. She has been in receipt of research funding from AstraZeneca and contributed to CRUK Cancer Research Horizons' filing of patent application WO/2017/144877. TGB has received research funding from Iterion Therapeutics, Diogenx and Trogenix. The other authors declare no competing interests. Funder Information Declared United Kingdom Medical Research Council , MR/X018512/1 Academy of Medical Sciences , SBF008\1034 UKRI Horizon , Halt-RONIN 10067052 Cancer Research UK, https://ror.org/054225q67 , PRCBTP-May24/100005 Cancer Research UK , HUNTER: A26813 Wellcome Trust, https://ror.org/029chgv08 , WT107492Z Cancer Research UK, https://ror.org/054225q67 , A17196 and A31287 Cancer Research UK , C596/A26855 European Research Council, https://ror.org/0472cxd90 , ERC-2020-ADG PancObese 10102064 Cancer Research UK , A29799 United Kingdom Medical Research Council , MC_PC_20142 Cancer Research UK, Wellcome Trust, and UK Medical Research Council , CC2073 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 03, 2026. 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