UHRF1 levels drive distinct senescent states in zebrafish liver cells
High UHRF1 expression causes stable senescence sensitive to Navitoclax, while cells with lower expression proliferate if tp53 is mutated.
EMBO reports · Magnani E et al. · Paper published 28 Sep 2026
In zebrafish hepatocytes, researchers examined how overexpressing the epigenetic regulator UHRF1 drives senescent cell diversity during preneoplastic liver cancer development. Early responses to UHRF1 overexpression included DNA damage, DNA methylome repatterning, retrotransposon derepression, cell cycle withdrawal, and senescence dependent on atm and tp53. Single-cell RNA sequencing revealed distinct senescent cell subsets, with some populations expressing immunogenic and anti-apoptotic genes while others expressed proliferation genes. The resulting phenotypes varied according to UHRF1 dosage. Hepatocytes with low UHRF1 levels re-entered the cell cycle and proliferated in tp53 mutants. In contrast, cells with high UHRF1 levels remained permanently arrested and were selectively cleared by the senolytic drug Navitoclax.
Why it matters
Senescence can both suppress and promote tumor development depending on cell fate and persistence. These findings demonstrate that epigenetic regulators can dictate senescent cell heterogeneity and determine susceptibility to senolytic therapies.
Caveats
The experiments were restricted to a preneoplastic liver model in zebrafish hepatocytes, so findings may not translate directly to mammalian or human senescence.
Written from the paper’s abstract, and every claim checked against it before publishing. Read the paper for the full methods and data.
The paper
UHRF1 overexpression generates distinct senescent states with different Tp53 dependencies
Magnani E, Chen C, Macchi F et al.
EMBO reports · 28 Sep 2026 · Peer-reviewed
- Relevance
- Relevant
- News value
- Notable
- Evidence
- Model organisms
- Status
- Peer-reviewed
More on Cellular senescence
See allDasatinib and quercetin reduce liver fibrosis in a phase-2 MASH trial
The senolytic combination improved liver fibrosis without disease worsening in nearly half of treated participants while lowering cellular senescence markers.
Nature metabolism · Koning M et al.
A distinct p21-driven macrophage senotype accumulates during aging and liver disease
Researchers identified a p53-p21-Cyclin D2 axis that governs senescent macrophages in mice and human liver cirrhosis and can be cleared with senolytics.
bioRxiv · Torres G et al.
DNA methylation proxies of senescence markers track human disease and mortality
The new blood-based tools estimate senescence gene activity to predict incident diseases, all-cause mortality, and clinical treatment responses.
medRxiv · Simpson DJ et al.
Bispecific T cell engager eliminates senescent cells in mice and nonhuman primates
Monitored by serum transaminase levels, low doses of the drug alleviated age-related pathologies without causing the hepatotoxicity seen at higher doses.
Aging cell · Deng J et al.
A deep learning score for cellular senescence predicts human mortality and disease risk
The proteomic biomarker tracked chronic illness risk in the UK Biobank and shifted following an 18-month multimodal exercise intervention.
Aging cell · Zhao S et al.