Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction
Senescent hepatocytes accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD) and are linked to worse clinical outcomes. However, their heterogeneity and lack of specific markers have made them difficult to target therapeutically. Here, we define a senescent hepatocyte gene signature (SHGS) using in vitro and in vivo models and show that it tracks with MASLD progression/regression across mouse models and large human cohorts. Single-nucleus RNA-sequencing and functional studies reveal that SHGS+ hepatocytes originate from p21+ cells, lose key liver functions and release factors that drive disease progression. One such factor, GDF15, increases in circulation alongside SHGS+ burden and disease progression. Through chemical screening, we identify senolytics that selectively eliminate SHGS+ hepatocytes and improve MASLD in male mice. Notably, SHGS enrichment also correlates with dysfunction in other organs. These findings establish SHGS+ hepatocytes as key drivers of MASLD and highlight a potential therapeutic strategy for targeting senescent cells in liver disease and beyond.
Authors
- Simon G. Gregory (ORCID: https://orcid.org/0000-0002-7805-1743)
- Manal F. Abdelmalek (ORCID: https://orcid.org/0000-0002-5001-8618)
- Anna Mae Diehl (ORCID: https://orcid.org/0000-0003-1859-089X)
- Ji Hye Jun (ORCID: https://orcid.org/0000-0001-5716-8128)
- Steven S. Pullen
- Seh Hoon Oh (ORCID: https://orcid.org/0009-0006-3817-936X)
- Vaibhav Jain (ORCID: https://orcid.org/0000-0003-2394-3426)
- Ana Ferreira (ORCID: https://orcid.org/0000-0002-9388-9958)
- Guannan Gao (ORCID: https://orcid.org/0000-0001-6383-6751)
- Liuyang Wang (ORCID: https://orcid.org/0000-0001-9556-2361)
- Qiaojuan Zhang (ORCID: https://orcid.org/0000-0003-4260-8754)
- Jon Hill
- David S. Umbaugh (ORCID: https://orcid.org/0000-0002-5327-9020)
- Kuo Du (ORCID: https://orcid.org/0000-0002-1446-4653)
- Dennis C. Ko (ORCID: https://orcid.org/0000-0002-0113-5981)
- Rajesh Kumar Dutta (ORCID: https://orcid.org/0000-0002-1394-0961)
- Nanqi Ren
Institutions
- Duke University (US)
- Mayo Clinic in Arizona (US)
- Boehringer Ingelheim (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-28
- DOI
- https://doi.org/10.1038/s41467-025-57616-w
- Citations
- 25
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 33.85
Funders
- National Institute on Alcohol Abuse and Alcoholism
- National Institute of Diabetes and Digestive and Kidney Diseases