The IKKβ‐USP30‐ACLY Axis Controls Lipogenesis and Tumorigenesis

Background and Aims Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death that develops as a consequence of obesity, cirrhosis, and chronic hepatitis. However, the pathways along which these changes occur remain incompletely understood. Approach and Results In this study, we show that the deubiquitinase USP30 is abundant in HCCs that arise in mice maintained on high‐fat diets. IKKβ phosphorylated and stabilized USP30, which promoted USP30 to deubiquitinate ATP citrate lyase (ACLY) and fatty acid synthase (FASN). IKKβ also directly phosphorylated ACLY and facilitated the interaction between USP30 and ACLY and the latter’s deubiquitination. In HCCs arising in DEN/CCl 4 ‐treated mice, USP30 deletion attenuated lipogenesis, inflammation, and tumorigenesis regardless of diet. The combination of ACLY inhibitor and programmed death ligand 1 antibody largely suppressed chemical‐induced hepatocarcinogenesis. The IKKβ‐USP30‐ACLY axis was also found to be up‐regulated in human HCCs. Conclusions This study identifies an IKKβ‐USP30‐ACLY axis that plays an essential and wide‐spread role in tumor metabolism and may be a potential therapeutic target in HCC.