芳基乙酰胺脱乙酰酶 (AADAC) 催化含有酯键和酰胺键的小分子的水解。最近，有报道称AADAC可以抑制癌细胞中活性氧的产生。本研究旨在阐明AADAC对氧化应激所致药物性肝损伤的保护作用，并探讨其分子机制。腹腔注射四氯化碳可导致 Aadac 敲除 (KO) 小鼠（血浆丙氨酸转氨酶水平：19,381±10,578 U/L）比野生型（WT）小鼠（7219 ± 4729 U/L）更严重的肝损伤。与 WT 小鼠相比，Aadac KO 小鼠更严重的肝损伤伴随着更高的肝脏丙二醛和抗氧化基因 mRNA 水平。使用铁死亡抑制剂去铁胺或铁他汀-1 进行预处理后，Aadac KO 小鼠血浆丙氨酸转氨酶水平的增加得到显着抑制，表明 Aadac 缺乏会增加铁死亡的易感性。免疫沉淀和随后的蛋白质组分析表明 AADAC 与铜蓝蛋白 (CP) 相互作用，后者将二价铁氧化为三价铁。 Aadac KO 小鼠的肝脏 CP 活性显着低于 WT 小鼠，导致 Aadac KO 小鼠的肝脏亚铁水平升高。 Huh-7 细胞中人 AADAC 的过表达通过抑制二价铁积累显着减弱四氯化碳诱导的细胞毒性，表明 AADAC 与 CP 相互作用以抑制肝二价铁积累。在对乙酰氨基酚诱导的肝损伤小鼠中也观察到了 Aadac 在铁死亡中的保肝作用。这项研究证明了 AADAC 在预防由肝毒物、四氯化碳和对乙酰氨基酚引起的铁死亡方面的新功能。© 2024。作者获得 Springer-Verlag GmbH 德国（Springer Nature 旗下公司）的独家许可。

Arylacetamide deacetylase (AADAC) catalyzes the hydrolysis of small molecules containing ester and amide bonds. Recently, it has been reported that AADAC can suppress reactive oxygen species production in cancer cells. This study aimed to elucidate the possibility that AADAC protects against drug-induced liver injury accompanied by oxidative stress and to explore its molecular mechanisms. Intraperitoneal administration of carbon tetrachloride induced significantly more severe liver injury in Aadac knockout (KO) mice (plasma alanine aminotransferase level: 19,381 ± 10,578 U/L) than in wild-type (WT) mice (7219 ± 4729 U/L). More severe liver injury in Aadac KO mice was accompanied by higher hepatic malondialdehyde and antioxidant gene mRNA levels than those in WT mice. The increase in plasma alanine aminotransferase levels in Aadac KO mice was substantially suppressed by pretreatment with the ferroptosis inhibitors deferoxamine or ferrostatin-1, suggesting that Aadac deficiency increases susceptibility to ferroptosis. Immunoprecipitation followed by proteomic analysis revealed that AADAC interacts with ceruloplasmin (CP), which oxidizes ferrous iron to ferric iron. Hepatic CP activity was significantly lower in Aadac KO mice than that in WT mice, resulting in elevated hepatic ferrous iron levels in Aadac KO mice. Overexpression of human AADAC in Huh-7 cells significantly attenuated carbon tetrachloride-induced cytotoxicity by suppressing ferrous iron accumulation, suggesting that AADAC interacts with CP to suppress hepatic ferrous iron accumulation. The hepatoprotective role of Aadac in ferroptosis was also observed in mice with acetaminophen-induced liver injury. This study demonstrates a novel function of AADAC in protecting against ferroptosis induced by hepatotoxicants, carbon tetrachloride and acetaminophen.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.