Acetaminophen (APAP) overdose has been considered responsible for the drug-induced liver injury for many years. Ferroptosis is defined as an iron-dependent form of cell death associated with lipid peroxide accumulation. Ferroptosis is involved in APAP-induced acute liver failure, and UTI is an effective drug treatment for acute liver failure. Thus, we aimed to determine whether UTI protects the liver against APAP-induced acute liver failure by decreasing ferroptosis-induced lipid peroxide accumulation. C57BL/6 mice and LO2 cell line were treated with UTI before and after the exposure to APAP. Liver tissues and LO2 cells were collected for biochemical assessment of molecular parameters. APAP-induced upregulation of ferroptotic events (iron content), lipid hydroperoxides (ROS production, MDA, and 4-HNE), and depletion of GSH were effectively relieved by ferrostatin-1 (Fer-1), a ferroptosis inhibitor, and UTI. UTI blocked ferroptosis-induced lipid peroxide accumulation by promoting nuclear translocation of NRF2 to activate its downstream targets (HO-1). An increased expression or knockdown of of SIRT1 influenced the UTI effect on the NRF2 pathway and had an impact on lipid accumulation. Overall, UTI plays a role in mitigation of APAP-induced acute liver injury by inhibiting ferroptosis-induced lipid peroxide accumulation, and the effect of UT1 was mediated by the NRF2/HO-1 pathway and SIRT1 expression.
Keywords: NRF2; SIRT1; Ulinastatin; acetaminophen; ferroptosis; hepatotoxicity.
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