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

Kuo Du (), David S. Umbaugh, Wang Liuyang, Ji Hye Jun, Rajesh K. Dutta, Seh Hoon Oh, Niansheng Ren, Qiaojuan Zhang, Dennis C. Ko, Ana Ferreira, Jon Hill, Guannan Gao, Steven S. Pullen, Vaibhav Jain, Simon Gregory, Manal F. Abdelmalek and Anna Mae Diehl ()
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Kuo Du: Duke University
David S. Umbaugh: Duke University
Wang Liuyang: Duke University
Ji Hye Jun: Duke University
Rajesh K. Dutta: Duke University
Seh Hoon Oh: Duke University
Niansheng Ren: Duke University
Qiaojuan Zhang: Duke University
Dennis C. Ko: Duke University
Ana Ferreira: Boehringer Ingelheim Pharmaceuticals Inc
Jon Hill: Boehringer Ingelheim Pharmaceuticals Inc
Guannan Gao: Boehringer Ingelheim Pharmaceuticals Inc
Steven S. Pullen: Boehringer Ingelheim Pharmaceuticals Inc
Vaibhav Jain: Duke University
Simon Gregory: Duke University
Manal F. Abdelmalek: Mayo Clinic
Anna Mae Diehl: Duke University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57616-w

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