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

## TL;DR

Caspase-2 deficiency in mice leads to liver polyploidy, inflammation, and increased risk of liver cancer with age.

## Contribution

The study reveals caspase-2's role in preventing pathogenic polyploidy and liver cancer through its enzymatic activity.

## Key findings

- Caspase-2 loss causes early-onset hepatocyte hyperpolyploidy and liver inflammation.
- Caspase-2 deficiency increases spontaneous hepatocellular carcinoma in aged mice.
- Proteomic profiling identifies a polyploidy-associated signature linked to liver disease and malignancy.

## 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.

Caspase-2 inactivation promotes pathogenic hepatocyte polyploidy and age-related liver cancer.