2. Academic Validation
  3. Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction

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

Affiliations

  • 1 Department of Medicine, Duke University, Durham, NC, USA. kuo.du@duke.edu.
  • 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. annamae.diehl@duke.edu.
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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