Xu Jun, Zhao Luying, Zhang Xiangting, Ying Kanglei, Zhou Ruoru, Cai Weimin, Wu Xiao, Jiang Haoran, Xu Qian, Miao Dan, Zeng Yuan, Yu Fujun
Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Urology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Ecotoxicol Environ Saf. 2023 Aug 7;262:115331. doi: 10.1016/j.ecoenv.2023.115331.
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.
对乙酰氨基酚（APAP）过量长期以来一直被认为是药物性肝损伤的主要原因。铁死亡是一种由铁依赖性脂质过氧化介导的程序性细胞死亡。内质网（ER）应激是由内质网中未折叠或错误折叠蛋白质的积累引发的一种全身性反应。铁死亡和内质网应激已被证明与APAP诱导的急性肝损伤（ALI）的进展有关。据报道，红景天苷可预防APAP诱导的ALI，但其潜在机制尚不清楚。在本研究中，雄性C57BL/6 J小鼠腹腔注射APAP（500 mg/kg）以诱导ALI模型。在给予APAP前2小时腹腔注射100 mg/kg剂量的红景天苷。APAP注射后12小时处死小鼠，获取小鼠的肝脏和血清进行组织学和生化分析。体外实验使用AML12细胞。结果表明，红景天苷通过抑制阳离子转运调节因子同源物1（CHAC1）减轻谷胱甘肽降解以减轻铁死亡，同时抑制PERK-eIF2α-ATF4轴介导的内质网应激，从而减轻APAP诱导的ALI。然而，PERK激活剂CCT020312和ATF4的过表达抑制了红景天苷对CHAC1介导的铁死亡的保护作用。除此之外，红景天苷激活AMPK/SIRT1信号通路对APAP诱导的ALI具有保护作用。有趣的是，选择性抑制SIRT1可改善红景天苷对内质网应激和铁死亡的保护作用。总体而言，红景天苷通过激活AMPK/SIRT1信号通路抑制ATF4-CHAC1轴中内质网应激介导的铁死亡，在减轻APAP诱导的ALI中起重要作用。
