Genistein Ameliorates Non-alcoholic Fatty Liver Disease by Targeting the Thromboxane A₂ Pathway

Non-alcoholic fatty liver disease (NAFLD) is now a public health issue worldwide, but no drug has yet received approval. Genistein, an isoflavonoid derived from soybean, ameliorates high-fat-diet-induced NAFLD in mice, but the molecular underpinnings remain largely elusive. Arachidonic acid (AA) is a major ingredient of animal fats, and the AA cascade has been implicated in chronic inflammation. In this study, we investigated whether genistein was against NAFLD by targeting the AA cascade. Using a mouse model, we showed that genistein supplementation improved high-fat-diet-induced NAFLD by normalizing hepatomegaly, liver steatosis, aminotransferase abnormalities, and glucose tolerance. The thromboxane A₂ (TXA₂) pathway was aberrantly active in NAFLD, evidenced by an elevation of circulating TXA₂ and hepatic thromboxane A₂ receptor expression. Mechanistically, we found that genistein directly targeted cyclooxygenase-1 activity as well as its downstream TXA₂ biosynthesis, while the TXA₂ pathway might mediate NAFLD progression by impairing insulin sensitivity. Taken together, our study revealed a crucial pathophysiological role of the TXA₂ pathway in NAFLD and provided an explanation as to how genistein was against NAFLD progression.