Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction
Kuo Du, David S. Umbaugh, Liuyang Wang, Ji Hye Jun, Rajesh Kumar Dutta, Seh Hoon Oh, Niansheng Ren, Qiaojuan Zhang, Dennis C. Ko, Ana Ferreira, Jon Hill, Guannan Gao, Steven S. Pullen, Vaibhav Jain, Simon G. Gregory, Manal F. Abdelmalek, Anna Mae Diehl
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. MASLD is a growing global health concern. Here, the authors define a senescent hepatocyte gene signature (SHGS), demonstrate its clinical relevance, and identify senolytic therapies that selectively eliminate SHGS+ hepatocytes to improve MASLD and systemic health.