Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Aspirin eugenol ester attenuates alcoholic liver injury via the NRF2/SLC7A11/GPX4 pathway-mediated ferroptosis suppression.
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Zhang Zhi-Jie, Tao Qi, Feng Ji, Fan Li-Ping, Shen Dong-Shuai, Yang Ya-Jun, Li Jian-Yong
Аннотация
BACKGROUND: Alcoholic liver injury (ALI) is a prevalent chronic liver disease worldwide and represents a major public health burden. Previous pharmacological and pharmacodynamic studies have indicated that aspirin eugenol ester (AEE) exerts multiple pharmacological activities, including protective effects against non-alcoholic fatty liver disease. However, whether AEE can ameliorate ALI and the underlying mechanisms remain unclear.
PURPOSE: This study sought to explore the protective effects of AEE on ALI and to delineate the associated molecular mechanisms.
METHODS: This study investigated the protective effects of AEE against ALI using both in vitro and in vivo models, with a particular focus on elucidating its molecular mechanisms.
RESULTS: In cellular models, AEE significantly alleviated ethanol- and erastin-induced cytotoxicity and morphological damage, while markedly reversing abnormalities in superoxide dismutase (SOD) activity, malondialdehyde (MDA) levels, Fe2+ accumulation, reactive oxygen species (ROS) levels, 4-Hydroxynonenal levels and lipid peroxidation. Mechanistically, AEE attenuated ethanol-induced ferroptosis by activating the NRF2/SLC7A11/GPX4 antioxidant axis. This result was validated in primary mouse hepatocytes. In animal models, AEE markedly improved alcohol-induced metabolic disturbances, including dyslipidemia, glucose disorders, and hepatic steatosis, while restoring hepatic redox homeostasis and ethanol metabolism through upregulation of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) and suppression of CYP2E1. Consistently, AEE enhanced NRF2 signaling and ferroptosis resistance in liver tissues, as evidenced by increased expression of SLC7A11, GPX4, ferritin, and HO-1, along with reduced expression of BAP1, Keap1 and P53.
CONCLUSIONS: AEE exerts a potent protective effect against ALI by attenuating ethanol-induced ferroptosis via activation of the NRF2/SLC7A11/GPX4 signaling pathway, thereby improving hepatic metabolic homeostasis.
PURPOSE: This study sought to explore the protective effects of AEE on ALI and to delineate the associated molecular mechanisms.
METHODS: This study investigated the protective effects of AEE against ALI using both in vitro and in vivo models, with a particular focus on elucidating its molecular mechanisms.
RESULTS: In cellular models, AEE significantly alleviated ethanol- and erastin-induced cytotoxicity and morphological damage, while markedly reversing abnormalities in superoxide dismutase (SOD) activity, malondialdehyde (MDA) levels, Fe2+ accumulation, reactive oxygen species (ROS) levels, 4-Hydroxynonenal levels and lipid peroxidation. Mechanistically, AEE attenuated ethanol-induced ferroptosis by activating the NRF2/SLC7A11/GPX4 antioxidant axis. This result was validated in primary mouse hepatocytes. In animal models, AEE markedly improved alcohol-induced metabolic disturbances, including dyslipidemia, glucose disorders, and hepatic steatosis, while restoring hepatic redox homeostasis and ethanol metabolism through upregulation of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) and suppression of CYP2E1. Consistently, AEE enhanced NRF2 signaling and ferroptosis resistance in liver tissues, as evidenced by increased expression of SLC7A11, GPX4, ferritin, and HO-1, along with reduced expression of BAP1, Keap1 and P53.
CONCLUSIONS: AEE exerts a potent protective effect against ALI by attenuating ethanol-induced ferroptosis via activation of the NRF2/SLC7A11/GPX4 signaling pathway, thereby improving hepatic metabolic homeostasis.