The IKKβ‐USP30‐ACLY Axis Controls Lipogenesis and Tumorigenesis

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. In this study, we show that the deubiquitinase USP30 is abundant in HCCs that arise in mice maintained on high fat diets (HFDs). IKKbeta phosphorylated and stabilized USP30, which promoted USP30 to deubiquitinate ATP citrate lyase (ACLY) and fatty acid synthase (FASN). IKKbeta also directly phosphorylated ACLY and facilitated the interaction between USP30 and ACLY and the latter's deubiquitination. In HCCs arising in DEN/CCl4 -treated mice, USP30 deletion attenuated lipogenesis, inflammation and tumorigenesis irrespective of diet. The combination of ACLY inhibitor and PD-L1 antibody largely suppressed chemical-induced hepatocarcinogenesis. The IKKbeta-USP30-ACLY axis was also found to be upregulated in human HCCs. Conclusion: This study identifies a new IKKbeta-USP30-ACLY axis that plays an essential and wide-spread role in tumor metabolism and may be a potential therapeutic target in HCC.