Artesunate reduces oxidative stress and inflammation in NAFLD by activating the Nrf2 pathway

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disorder worldwide, characterized by progression from simple steatosis to inflammatory liver injury. Artesunate (AS), an antimalarial agent derived from Artemisia annua, possesses well-documented metabolic regulatory, antioxidant, and anti-inflammatory properties. This study comprehensively evaluated the therapeutic effects of AS on NAFLD pathogenesis and elucidated its underlying molecular mechanisms using integrated experimental approaches. AS administration significantly mitigated NAFLD progression, as reflected by marked reductions in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, substantial attenuation of lobular inflammation, and notable improvement in hepatocellular ballooning, collectively resulting in decreased NAFLD activity scores. Network pharmacology analysis further identified oxidative stress and inflammatory pathways as major molecular targets of AS intervention. Mechanistic investigations revealed that AS-mediated hepatoprotection is primarily driven by strong activation of the Nrf2 antioxidant pathway, evidenced by enhanced nuclear translocation of Nrf2 and consequent upregulation of key downstream antioxidant enzymes, including superoxide dismutase (SOD) and glutathione (GSH). The essential role of Nrf2 signaling was conclusively validated through genetic and pharmacological inhibition studies, which completely abolished the therapeutic effects of AS on hepatic injury and oxidative imbalance. Taken together, these findings provide robust preclinical evidence that AS confers multi-dimensional protection against NAFLD progression through targeted activation of the Nrf2 pathway, offering new mechanistic insight into NAFLD treatment and underscoring the strong translational potential of AS given its established clinical safety profile.