The current investigation, aimed to determine whether CDKN1A is essential or dispensable for HCC induction in SOCS1-deficient mice, revealed an intricate interplay between SOCS3, p53, and CDKN1A that contributes to oncogenic NRF2 activation in SOCS1-deficient hepatocytes. Here, CDKN1A is linked to hepatocellular carcinoma.