UFMylation deficiency in hepatocytes activates the KEAP1-NRF2 pathway and contributes to hepatocarcinogenesis

The Kelch-like ECH-associated protein 1 (KEAP1) - Nuclear factor erythroid 2-related factor 2 (NRF2) pathway plays a central role in maintaining cellular redox balance, aberrant activation of the KEAP1-NRF2 pathway is involved in a variety of human malignant tumors including hepatocellular carcinoma. However, the underlying mechanisms remain unclear. UFMylation is a type of ubiquitin-like modifications with important biological functions, its deficiency is implicated in several pathogenesis. In this study, we show that hepatocyte specific Ufl1 knockout in mice results in several hepatic pathological alterations and promotes the development of diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Furthermore, we identified KEAP1 as an UFMylation substrate, and deficiency in UFMylation modification resulted in ubiquitin-mediated degradation of KEAP1, and subsequent nuclear accumulation of NRF2, and activation of the KEAP1-NRF2 pathway. Consistently, we found that UFL1 expression is decreased and positively correlated with the level of KEAP1 in liver cancer samples. Our results suggest that UFL1 plays an important role in liver pathophysiology, in part by regulating the KEAP1-NRF2 pathway, thus provides novel insights into the molecular basis of hepatocarcinogenesis.