Alla Y. Karpova, Xiang Li, Chien‐Wei Peng, Kelsey Gallant, Daniel R. Rapp, Daniel M. Alligood, Andrew J. Houston, Alex Park, André Luiz N. Targino da Costa, Wen-hung Chou, Michael D. Iglesia, John M. Herndon, Kathleen Byrnes, Nataly Naser Al Deen, Preet Lal, Xiangwei Fang, Reyka G. Jayasinghe, Jeffrey A. Blatnik, William G. Hawkins, Dominic E. Sanford, J. Chris Eagon, Natasha Leigh, Maria Bernadette M. Doyle, L. Michael Brunt, William Chapman, Roheena Z. Panni, Darren R. Cullinan, Sherri R. Davies, Jun Guo, Matthew A. Wyczalkowski, Michael C. Wendl, Hong Zhang, Colin Martin, Brad W. Warner, Milan Chheda, Sheila A. Stewart, Feng Chen, Ryan Fields, Li Ding
Cellular senescence, a stress-induced program causing stable cell-cycle arrest, is a hallmark of liver aging, fibrosis, and cancer. However, the cell-type-specific mechanisms, spatial organization, and cancer-associated alterations in the liver remain unclear. We profiled 43 normal human livers spanning ages and fibrosis stages using a single-cell multiome, Xenium spatial transcriptomics, and CODEX, complemented by fibrotic mouse models and 24 colorectal cancer liver metastases. We found CDKN1A+ senescent hepatocytes, fibroblasts, cholangiocytes, and endothelial cells associated with age, liver disease, or cancer. Senescence differed between aged and fibrotic livers, with similar patterns in mice. Spatially, CDKN1A+ hepatocytes localized periportally, while SERPINE1+ aging-associated hepatocytes formed spatial clusters, potentially mediated by Claudins and THBS1. Fibrotic regions contained CXCL12+ senescent fibroblasts interacting with CXCR4+ immune cells. Chemotherapy intensified senescence in hepatocytes by 5-fold relative to aging and led to unique CDKN2A+ populations. Across conditions, senescent cells shared AP-1 activation, pro-inflammatory cytokines, and apoptosis resistance, suggesting therapeutic opportunities.