Mechanism of protecting hepatocytes in NAFLD through MST1-FOXO3a-SREBP2 pathway.

Non-alcoholic fatty liver disease (NAFLD) is a globally prevalent chronic liver condition, primarily characterized by excessive accumulation of fat within the liver. A pivotal factor in the progression of NAFLD is cholesterol deposition, which significantly exacerbates liver cell damage through the induction of endoplasmic reticulum (ER) stress. At the heart of this process is sterol regulatory element-binding protein 2 (SREBP2), a crucial transcription factor in cholesterol synthesis. The expression levels of SREBP2 are closely associated with the severity of NAFLD, marking it as a potential therapeutic target. In mouse liver, FOXO3a, a member of the forkhead box protein family, inhibits the expression of SREBP2. This regulation is further influenced by its phosphorylation by mammalian STE20-related kinase 1 (MST1). Our research has uncovered a novel pathway in a NAFLD model where MST1-induced phosphorylation facilitates the nuclear translocation of FOXO3a, leading to a subsequent inhibition of SREBP2 expression. This critical modulation not only curtails cholesterol synthesis but also mitigates cholesterol deposition, alleviates ER stress, and repairs liver cell damage. These findings highlight the MST1-FOXO3a-SREBP2 axis as a promising new target for NAFLD treatment strategies, offering potential pathways to ameliorate a disease that affects millions worldwide.