Toxicol Appl Pharmacol. 2026 May 15:117872. doi: 10.1016/j.taap.2026.117872. Online ahead of print.
ABSTRACT
Arylacetamide deacetylase (AADAC) is a drug-metabolizing enzyme that catalyzes the hydrolysis of clinical drugs containing an acetyl moiety. Recent in vitro studies have suggested that AADAC also reduces intracellular lipid accumulation; however, the underlying mechanism remains unclear. AADAC has been reported to decrease hepatic ferrous iron (Fe2+) levels, which are known to promote activation of the unfolded protein response. Excess unfolded protein response activation can lead to endoplasmic reticulum (ER) stress and subsequent hepatic steatosis. The aim of this study was to elucidate the role of AADAC in lipid metabolism under ER stress using Aadac knockout (KO) mice. ER stress was induced by intraperitoneal administration of tunicamycin (1.0 mg/kg) to wild-type (WT) mice and Aadac KO mice. Compared with WT mice, Aadac KO mice exhibited increased hepatic iron levels and oxidative stress, accompanied by elevated expression of ER stress-related genes, indicating that Aadac deficiency exacerbates iron-associated ER stress. Consistently, hepatic lipid accumulation was significantly greater in Aadac KO mice than in WT mice. Notably, pre-administration of the iron chelator deferoxamine (200 mg/kg, i.p.) attenuated ER stress and reduced hepatic lipid accumulation in Aadac KO mice to levels comparable to those in WT mice. Collectively, these findings demonstrate that AADAC protects the liver against lipid accumulation under ER stress conditions by regulating iron-dependent oxidative stress.
PMID:42142810 | DOI:10.1016/j.taap.2026.117872