[Elucidation of a Novel Protective Function of AADAC Against Drug-induced Liver Injury through Ferroptosis Suppression].

Drug-induced liver injury (DILI) remains a major cause of drug withdrawal from the market, and safety concerns in clinical settings. Reactive metabolites, primarily produced by cytochrome P450 enzymes, are known to induce oxidative stress and hepatotoxicity through covalent binding to macromolecules and the generation of reactive oxygen species. Recent evidence suggests that ferroptosis, an iron-dependent form of lipid peroxidation-mediated cell death, is involved in DILI triggered by compounds such as carbon tetrachloride (CCl4) and acetaminophen (APAP). Arylacetamide deacetylase (AADAC), a hepatic hydrolase previously recognized for its role in drug metabolism, has recently been implicated in tumor suppression and ROS regulation in cancer cells. In this study, our group explored whether AADAC exerts a protective effect against ferroptosis-associated liver injury. Using Aadac knockout (KO) mice, we demonstrated that CCl4, APAP, and amodiaquine induced more severe liver damage in the absence of Aadac, with elevated ferrous (Fe2+) levels, lipid peroxidation, and oxidative stress. We identified that Aadac interacts with ceruloplasmin, a ferroxidase that converts Fe2+ to ferric (Fe3+), thereby limiting ferroptosis. Notably, this function of Aadac was independent of its enzymatic activity. Furthermore, human AADAC overexpression in Huh-7 cells similarly reduced intracellular Fe2+ levels and conferred protection against CCl4-induced cytotoxicity in a ceruloplasmin-dependent manner. These findings reveal a novel, non-catalytic role for AADAC in iron homeostasis and ferroptosis suppression, suggesting its clinical significance in DILI susceptibility and therapy.