RNA-binding protein CLUH ameliorates metabolic-associated steatohepatitis pathogenesis by maintaining ER homeostasis

CLUH, an RNA-binding protein (RBP), is known to regulate liver metabolism under conditions of acute nutrient stress. However, its role in metabolic dysfunction-associated steatotic liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH) remains unknown. Here, we show that CLUH is downregulated in the methionine-choline-deficient (MCD) mouse model of MASH, as well as in MAFLD and MASH patients. Whereas overexpression of CLUH alleviates hepatic lipid accumulation, fibrosis, and serum AST and ALT levels induced by the MCD diet. Mechanistically, we found that CLUH regulates mitochondrial health, endoplasmic reticulum stress, and cell death by regulating Agxt2 expression. Collectively, our findings identify CLUH as a novel regulator of ER homeostasis and a potential target to treat MASH.