Salidroside ameliorates acetaminophen-induced acute liver injury through the inhibition of endoplasmic reticulum stress-mediated ferroptosis by activating the AMPK/SIRT1 pathway

Jun Xu; Luying Zhao; Xiangting Zhang; Kanglei Ying; Ruoru Zhou; Weimin Cai; Xiao Wu; Haoran Jiang; Qian Xu; Dan Miao; Yuan Zeng; Fujun Yu

doi:10.1016/j.ecoenv.2023.115331

Salidroside ameliorates acetaminophen-induced acute liver injury through the inhibition of endoplasmic reticulum stress-mediated ferroptosis by activating the AMPK/SIRT1 pathway

Ecotoxicol Environ Saf. 2023 Aug 7:262:115331. doi: 10.1016/j.ecoenv.2023.115331. Online ahead of print.

Authors

Jun Xu¹, Luying Zhao¹, Xiangting Zhang¹, Kanglei Ying¹, Ruoru Zhou¹, Weimin Cai¹, Xiao Wu¹, Haoran Jiang², Qian Xu¹, Dan Miao¹, Yuan Zeng³, Fujun Yu⁴

Affiliations

¹ Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
² Department of Urology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
³ Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: zengyuan121388@163.com.
⁴ Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: yufujun@wmu.edu.cn.

PMID: 37556956
DOI: 10.1016/j.ecoenv.2023.115331

Abstract

Acetaminophen (APAP) overdose has long been considered a major cause of drug-induced liver injury. Ferroptosis is a type of programmed cell death mediated by iron-dependent lipid peroxidation. Endoplasmic reticulum (ER) stress is a systemic response triggered by the accumulation of unfolded or misfolded proteins in the ER. Ferroptosis and ER stress have been proven to contribute to the progression of APAP-induced acute liver injury (ALI). It was reported that salidroside protects against APAP-induced ALI, but the potential mechanism remain unknown. In this study, male C57BL/6 J mice were intraperitoneally (i.p.) injected APAP (500 mg/kg) to induce an ALI model. Salidroside was i.p. injected at a dose of 100 mg/kg 2 h prior to APAP administration. Mice were sacrificed 12 h after APAP injection and the liver and serum of the mice were obtained for histological and biochemistry analysis. AML12 cells were used in in vitro assays. The results indicated that salidroside mitigated glutathione degradation via inhibiting cation transport regulator homolog 1 (CHAC1) to attenuate ferroptosis, and simultaneously suppressing PERK-eIF2α-ATF4 axis-mediated ER stress, thus alleviating APAP-induced ALI. However, PERK activator CCT020312 and overexpression of ATF4 inhibited the protective function of salidroside on CHAC1-mediated ferroptosis. Besides this, activation of the AMPK/SIRT1 signaling pathway by salidroside was demonstrated to have a protective effect against APAP-induced ALI. Interestingly, selective inhibition of SIRT1 ameliorated the protective effects of salidroside on ER stress and ferroptosis. Overall, salidroside plays a significant part in the mitigation of APAP-induced ALI by activating the AMPK/SIRT1 signaling to inhibit ER stress-mediated ferroptosis in the ATF4-CHAC1 axis.

Keywords: AMP-activated protein kinase; Acute liver injury; Endoplasmic reticulum stress; Ferroptosis; SIRT1; Salidroside.