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Abstract

Background Nonalcoholic fatty liver disease (NAFLD) is a global health challenge lacking effective treatments. Gastrodin (GAS), a major phenolglucoside from Gastrodia elata Blume (Orchidaceae), exhibits multiple beneficial properties but its potential role in NAFLD through ferroptosis remains unclear. Objective To investigate the therapeutic effects of GAS on NAFLD and clarify the underlying molecular mechanisms. Methods We established NAFLD models using high-fat diet (HFD)-fed mice and HepG2 cells treated with palmitic acid (PA) and oleic acid (OA). Therapeutic effects were assessed via histopathological and biochemical analyses. Molecular mechanisms and drug targets were investigated using co-immunoprecipitation (Co-IP), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and dual-luciferase reporter assays. Results GAS treatment significantly reduced hepatic inflammation and lipid accumulation, leading to improved metabolic parameters. Additionally, GAS decreased iron overload and oxidative stress markers, restored antioxidant defenses, and preserved mitochondrial function. Mechanistically, interaction assays revealed that GAS directly binds to Keap1, disrupting the Keap1/Nrf2 complex, promoting Nrf2 nuclear translocation, and enhancing the expression of target genes FSP1 and GPX4 . Conclusion GAS demonstrates significant promise as a therapeutic agent for NAFLD by inhibiting hepatic ferroptosis via direct targeting of the Keap1/Nrf2 signaling pathway.