AbstractNonalcoholic steatohepatitis (NASH) is the most severe and progressive form of nonalcoholic fatty liver disease (NAFLD), which can lead to life-threatening conditions, however, there is still no approved drug for the treatment of NASH. In this study we used human-like NASH mouse model and treated orally with isorhamnetin at a dose of 50 mg/kg to analyze the effect of isorhamnetin on the progression of NASH. NASH-induced mice represented severe steatosis with inflammation, and fibrosis in liver accompanied with high level of liver injury markers in serum. Isorhamnetin treatment reduced intrahepatic lipid accumulation and TG content by inhibiting de novo lipogenic pathway in NASH-induced mice. Consistent with this, isorhamnetin-treated NASH mice showed improved liver injury markers, reduced collagen deposition as well as decreased gene expression of fibrogenic markers. Taken together, here we showed for the first time that synthesized isorhamnetin alleviates pathologic features of NASH and thus can potentially contribute to NASH drug development.