Caspase-2 deficiency drives pathogenic liver polyploidy and increases age-associated hepatocellular carcinoma in mice

Dorstyn, L; Lim, Y; Scanlan, J; McLennan, E; De Bellis, D; Katschner, M; Finnie, J; Emery-Corbin, S; Yousef, J; Dagley, LF; Kok, CH; Shah, SS; Takahashi, C; Febbraio, MA; Kumar, S

Author(s): Dorstyn, L; Lim, Y; Scanlan, J; McLennan, E; De Bellis, D; Katschner, M; Finnie, J; Emery-Corbin, S; Yousef, J; Dagley, LF; Kok, CH; Shah, SS; Takahashi, C; Febbraio, MA; Kumar, S;
Details: Publication Year 2026-01-02,Volume 12,Issue #1,Page eaeb2571
Journal Title: Science Advances
Abstract: Hepatocyte polyploidization promotes liver homeostasis by enhancing resistance to cellular stress. Caspase-2, a proapoptotic protease, restricts polyploidization by deleting polyploid and aneuploid cells. While caspase-2 protects against diet-induced hepatic injury, it also acts as a tumor suppressor by controlling genomic instability and oxidative stress. To investigate these roles, we assessed hepatic ploidy dynamics, liver damage, and age-associated tumorigenesis in caspase-2-deficient and catalytically inactive mutant mice. We found that caspase-2 loss promotes early-onset hepatocyte hyperpolyploidy, accompanied by progressive liver inflammation, fibrosis, oxidative liver damage, ferroptosis, and higher incidence of spontaneous hepatocellular carcinoma in aged animals. Proteomic profiling revealed a pathogenic polyploidy-associated signature associated with caspase-2 deficiency and increased predisposition to liver disease and malignancy. These findings establish caspase-2 enzymatic activity as a critical regulator of hepatic genome stability and preventing age-related liver cancer that strongly argue against therapeutic caspase-2 inhibition as a strategy for managing liver injury or cancer risk.
Publisher: AAAS
Keywords: Animals; *Caspase 2/deficiency/genetics/metabolism; *Polyploidy; Mice; *Carcinoma, Hepatocellular/pathology/genetics/metabolism/etiology; *Liver Neoplasms/pathology/genetics/metabolism/etiology; *Liver/pathology/metabolism; Hepatocytes/metabolism/pathology; *Aging/pathology/genetics; Mice, Knockout; Oxidative Stress; Genomic Instability
Research Division(s): Advanced Technology and Biology
PubMed ID: 41477850
Publisher's Version: https://doi.org/10.1126/sciadv.aeb2571
Open Access at Publisher's Site: https://doi.org/10.1126/sciadv.aeb2571
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-29 02:00:42

Last Modified: 2026-01-29 02:01:03