Cellular senescence in human liver under normal aging and cancer
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.
Authors
- Xiangwei Fang (ORCID: https://orcid.org/0009-0004-8061-7680)
- Chien‐Wei Peng (ORCID: https://orcid.org/0000-0003-0744-7123)
- Alex Park (ORCID: https://orcid.org/0000-0002-2346-5949)
- Kathleen Byrnes (ORCID: https://orcid.org/0000-0002-9361-1120)
- Preet Lal (ORCID: https://orcid.org/0009-0005-8258-3688)
- Alla Y. Karpova (ORCID: https://orcid.org/0000-0001-5869-6336)
- Reyka G. Jayasinghe (ORCID: https://orcid.org/0000-0003-2368-4890)
- Natasha L. Leigh (ORCID: https://orcid.org/0000-0002-5691-4114)
- Sheila A. Stewart (ORCID: https://orcid.org/0000-0002-2260-9576)
- Darren R. Cullinan (ORCID: https://orcid.org/0000-0002-9161-212X)
- André Luiz N. Targino da Costa
- John M. Herndon (ORCID: https://orcid.org/0000-0002-8378-9654)
- Wen-hung Chou (ORCID: https://orcid.org/0000-0003-1941-3393)
- Roheena Z. Panni (ORCID: https://orcid.org/0000-0002-8144-6869)
- Ryan Fields
- Jeffrey A. Blatnik (ORCID: https://orcid.org/0000-0002-6295-5721)
- Kelsey Gallant
- Colin Martin
- William Chapman
- Milan Chheda
- William G. Hawkins
- Hong Zhang
- Jun Guo
- Dominic E. Sanford
- Matthew A. Wyczalkowski
- Michael D. Iglesia
- L. Michael Brunt
- Andrew J. Houston
- Daniel R. Rapp
- Daniel M. Alligood
- Li Ding
- Nataly Naser Al Deen
- Feng Chen
- Xiang Li
- Brad W. Warner
- Sherri R. Davies
- Maria Bernadette M. Doyle
- J. Chris Eagon
Institutions
- University of Massachusetts Chan Medical School (US)
- Washington University in St. Louis (US)
Publication Details
- Journal
- Cell Genomics
- Published
- 2026-01-22
- DOI
- https://doi.org/10.1016/j.xgen.2025.101133
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 0.00