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

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 profil

SUBMITTER: Dorstyn L 

PROVIDER: S-EPMC12757054 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature