NFE2L3 drives hepatocellular carcinoma cell proliferation by regulating the proteasome‐dependent degradation of ISGylated p53

Nuclear factor erythroid 2‐like 3 (NFE2L3) is a member of the cap ‘n’ collar basic‐region leucine zipper (CNC‐bZIP) transcription factor family that plays a vital role in modulating oxidation–reduction steady‐state and proteolysis. Accumulating evidence suggests that NFE2L3 participates in cancer development; however, little is known about the mechanism by which NFE2L3 regulates hepatocellular carcinoma (HCC) cell growth. Here, we confirmed that NFE2L3 promotes HCC cell proliferation by acting as a transcription factor, which directly induces the expression of proteasome and interferon‐stimulated gene 15 (ISG15) to enhance the proteasome‐dependent degradation of ISGylated p53. Post‐translational ISGylation abated the stability of p53 and facilitated HCC cell growth. In summary, we uncovered the pivotal role of NFE2L3 in promoting HCC cell proliferation during proteostasis. This finding may provide a new target for the clinical treatment of HCC.