Promotion of nonalcoholic steatohepatitis by RNA N⁶-methyladenosine reader IGF2BP2 in mice

Nonalcoholic steatohepatitis (NASH) has emerged as the major cause of end-stage liver diseases. However, an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies. In the present study, through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis, we identified IGF2BP2, an N⁶-methyladenosine modification reader, as a key regulator that promotes NASH progression in mice. Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis, inflammation, and fibrosis in mice, at least in part, by increasing Tab2 mRNA stability. Besides, hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers. Of potential clinical significance, IGF2BP2 expression is significantly upregulated in the livers of NASH patients. Moreover, knockdown of IGF2BP2 substantially alleviated liver injury, inflammation, and fibrosis in diet-induced NASH mice. Taken together, our findings reveal an important role of IGF2BP2 in NASH, which may provide a new therapeutic target for the treatment of NASH.