Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction

  • Nat Commun. 2025 Mar 28;16(1):3038. doi: 10.1038/s41467-025-57616-w.
Kuo Du  1 ,  David S Umbaugh  2 ,  Liuyang Wang  3 ,  Ji Hye Jun  2 ,  Rajesh K Dutta  2 ,  Seh Hoon Oh  2 ,  Niansheng Ren  2 ,  Qiaojuan Zhang  4 ,  Dennis C Ko  3 ,  Ana Ferreira  5 ,  Jon Hill  5 ,  Guannan Gao  5 ,  Steven S Pullen  5 ,  Vaibhav Jain  6 ,  Simon Gregory  6 ,  Manal F Abdelmalek  7 ,  Anna Mae Diehl  8
Affiliations
  • 1. Department of Medicine, Duke University, Durham, NC, USA. [email protected].
  • 2. Department of Medicine, Duke University, Durham, NC, USA.
  • 3. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
  • 4. Department of Neurology, Duke University, Durham, NC, USA.
  • 5. Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA.
  • 6. Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
  • 7. Department of Medicine, Mayo Clinic, Rochester, MN, USA.
  • 8. Department of Medicine, Duke University, Durham, NC, USA. [email protected].
PMID: 40155379 DOI: 10.1038/s41467-025-57616-w
Abstract

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.

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