文献类型：期刊文献

英文题名：Diallyl trisulfide activates Nrf2 by promoting S-sulfhydration of Keap1 to attenuate acute hypobaric hypoxia-induced lung injury

作者：Wang, Renjie[1,2];Wang, Yihao[2];Xu, Liang[2,3];Gao, Tianyi[1,2];Wu, Zhenhui[2,4];Liang, Keke[2,3];Yin, Xiubing[2,5];Li, Shubei[2,5];Tu, Bodan[1,2];Ta, Yanling[2,3];Lai, Chengcai[2,7];Li, Maoxing[2,3,6,7];Gao, Yue[1,2,4,5,6]

第一作者：Wang, Renjie

通信作者：Gao, Y[1];Lai, CC[2];Li, MX[2]

机构：[1]Tianjin Univ Tradit Chinese Med, Inst Tradit Chinese Med, Tianjin 301617, Peoples R China;[2]Beijing Inst Radiat Med, Beijing 100850, Peoples R China;[3]Gansu Univ Chinese Med, Coll Pharm, Lanzhou 730000, Peoples R China;[4]Jiangxi Univ Tradit Chinese Med, Sch Pharm, Nanchang 510006, Peoples R China;[5]Guangdong Pharmaceut Univ, Sch Pharm, Guangzhou 510006, Peoples R China;[6]First Med Ctr Chinese PLA Gen Hosp, Nephrol Inst Chinese Peoples Liberat Army, Beijing Key Lab Kidney Dis Res,Dept Nephrol, Natl Clin Res Ctr Kidney Dis,Natl Key Lab Kidney D, Beijing 100853, Peoples R China;[7]Beijing Inst Radiat Med, Beijing, Peoples R China

第一机构：Tianjin Univ Tradit Chinese Med, Inst Tradit Chinese Med, Tianjin 301617, Peoples R China

通信机构：[1]corresponding author), Tianjin Univ Tradit Chinese Med, Inst Tradit Chinese Med, Tianjin 301617, Peoples R China;[2]corresponding author), Beijing Inst Radiat Med, Beijing, Peoples R China.

年份：2026

卷号：156

外文期刊名：PHYTOMEDICINE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001762947800001)】；

基金：This work was supported by the Major science and technology projects of Xinjiang Uygur Autonomous Region (2022A03016 and subprogram 2022A03016-3) .

语种：英文

外文关键词：Diallyl trisulfide; Hypobaric Hypoxia; Lung injury; Ferroptosis; Sulfhydration; Nrf2

摘要：Background: Acute lung injury triggered by rapid ascent to high altitude represents a significant clinical challenge in high-altitude medicine. Its pathological progression is primarily driven by excessive oxidative stress and the subsequent induction of ferroptosis. Purpose: This study investigated the therapeutic potential of Diallyl Trisulfide (DATS), a natural sulfur-containing compound from garlic, in mitigating Acute lung injury induced by acute hypobaric hypoxia. Methods: In vivo, the anti-hypoxic efficacy of DATS was initially investigated using various acute hypoxia mouse models, and its protective effect against lung injury was further examined in an acute high-altitude hypoxia rat model. In vitro, the cytoprotective role of DATS in HPMECs was assessed under hypoxia induced by cobalt chloride (CoCl2), as well as upon treatment with the ferroptosis inducer Erastin or the mitochondrial inhibitor carbonyl cyanide m-chlorophenylhydrazone (CCCP). Moreover, the use of the apoptosis inhibitor Z-VAD-FMK and the necroptosis inhibitor Necrostatin-1 (Nec-1) as additional controls demonstrated that the anti-ferroptotic effect of DATS is specific and not mediated by other cell death pathways. Furthermore, both in vivo and in vitro, the Nrf2 inhibitor ML385 was employed to confirm that Nrf2 is a key mediator through which DATS regulates ferroptosis and attenuates lung injury. Finally, in vitro studies were conducted to elucidate the molecular mechanism by which DATS modifies critical cysteine residues on Keap1, leading to Nrf2 nuclear translocation and activation, thereby counteracting ferroptosis and protecting against lung injury. Results: In vivo experiments demonstrated that DATS significantly prolonged the survival time of mice under acute hypoxia, improved abnormal blood gas parameters in rats exposed to hypobaric hypoxia, alleviated histopathological lung damage. In vitro experiments demonstrated that DATS significantly enhanced cell viability. Furthermore, it effectively restored intracellular oxidative stress homeostasis and suppressed lipid peroxidation and iron accumulation. Mechanistically, DATS markedly increased the levels of HAS and total protein sulfhydration, and specifically induced sulfhydration of the Keap1 protein at cysteine 151 (Cys151). This modification disrupted the Keap1-Nrf2 interaction, thereby stabilizing Nrf2 protein and promoting its nuclear translocation. Subsequently, nuclear Nrf2 activated the expression of downstream antioxidant genes, including GPX4 and xCT, restored glutathione homeostasis, inhibited lipid peroxidation and iron accumulation, and ultimately counteracted the ferroptosis process. Conclusion: DATS protects against acute hypobaric hypoxia-induced lung injury by S-sulfhydrating Keap1, activating the Nrf2 pathway, enhancing cellular antioxidant defenses, and effectively inhibiting ferroptosis.