Oroxylin A ameliorates hepatic steatosis and non-alcoholic fatty liver disease through the regulation of CPT1A m6A methylation in hepatocytes.

Non-alcoholic fatty liver disease (NAFLD) is a chronic condition that is frequently observed worldwide and has become a threat to global public health. Excess accumulation of hepatic lipids contributes to NAFLD. Oroxylin A has attracted widespread attention because of its antioxidant and immunomodulatory activities. Nonetheless, its role in hepatic lipid metabolism remains unclear. In this work, in hepatocytes exposed to palmitic acid (PA), oroxylin A significantly reduced lipid accumulation by inhibiting lipogenesis. Mechanistic studies revealed that oroxylin A can regulate m6A demethylation-related carnitine O-palmitoyltransferase 1A (CPT1A) mRNA expression, which was confirmed by in vitro silencing of YTHDC1. Mouse liver responses to a high-fat diet (HFD) and oroxylin A administration were subsequently analyzed through an assessment of liver histology, hepatic lipid levels, lipogenesis, and m6A demethylation gene transcription levels. Oroxylin A mitigated lipid metabolism, improved liver inflammation and damage, and regulated YTHDC1-mediated m6A demethylation in the livers of mice. Overall, oroxylin A efficiently alleviated hepatic lipid metabolic disturbances in mice. Consequently, oroxylin A is a candidate anti-NAFLD agent.