Our data provide the first critical evidence that loss of caspase-2 or its enzymatic activity is adverse for liver homeostasis by promoting early liver hyperpolyploidy that is associated with a pathogenic polyploidy–associated liver disease (ppaLD) protein signature and increased predisposition to chronic hepatitis–like liver disease, ferroptosis, and HCC. This evidence concerns the gene CASP2 and hepatocellular carcinoma.