Galangin Ameliorates Acetaminophen-Induced Acute Liver Injury by Inhibiting Ferroptosis through the Prevention of Chaperone-Mediated Autophagic Degradation of FTH1

Hepatocellular ferroptosis is a key driver of acetaminophen (APAP)-induced acute liver injury (AILI). Although galangin has been reported to exert liver-protective effects by modulating ferroptosis, its role and mechanism in AILI remain poorly understood. In this study, galangin significantly attenuated APAP-induced liver injury and dysfunction. RNA-seq analysis suggested that galangin may mitigate AILI via ferroptosis- and autophagy-related pathways and identified FTH1 as a potential target. Molecular docking and CETSA confirmed a specific and stable interaction between galangin and FTH1. Furthermore, galangin significantly inhibited ferroptosis-related proteins (Cox2, Acsl4, and Lpcat3) and rescued antiferroptotic regulators (Gpx4, Slc7a11, Fsp1, and NADPH) in AILI mice, without altering autophagy-related proteins Ncoa4, LC3, and p62. Mechanistically, galangin inhibited the recognition and binding of HSC70 to FTH1 and downregulated the expression of LAMP2A, thereby reducing chaperone-mediated autophagy (CMA)-dependent degradation of FTH1 and ultimately inhibiting ferroptosis. Overall, this study supports galangin as a potential hepatoprotective supplement.