The E3 Ligase RNF8 Promotes Ubiquitination and Degradation of ChREBPα During Liver Stress Response

As the most common chronic liver disease, MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH) driven by accumulated metabolic and inflammatory stresses. We previously reported that liver ChREBPα protein is markedly downregulated in mouse models of diet-induced MASH and hepatotoxin-induced liver injury. Yet the impact of stress pathways on hepatocyte ChREBPα proteolysis has not been examined. Here, we show that a combined metabolic (palmitate, PA) and inflammatory (TNFα) stress signal promotes ubiquitination and proteasome-mediated degradation of ChREBPα in hepatocytes. More importantly, we identify the stress-induced E3 ligase RNF8 as interacting with and promoting ChREBPα ubiquitination and degradation in a JNK2-dependent manner. In vivo, acute depletion of JNK2 or RNF8 stabilizes ChREBPα in mouse liver, increases some but not all ChREBPα transcriptional targets, and reduces diet-induced liver steatosis, inflammation, and fibrosis. Overall, our findings reveal the biochemical machinery underlying stress-induced ChREBPα proteolysis and suggest that targeting RNF8-mediated ChREBPα ubiquitination could be a new strategy for treating MASH.