2-乙醇通过破坏由二甲基硫氧化物改善的内分泌网膜平衡来诱导肝毒性
Tzung-Hsin Chou1, Min-Hsiu Hu2, Kuo-Tai Hua3
1Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Emergency Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Biochimica et biophysica acta. Molecular basis of disease
|August 16, 2025
概括
2-乙醇 (2CE) 通过破坏内质网膜 (ER) 稳态和激活未折叠蛋白质反应 (UPR) 来引起肝损伤. 甲基二硫化物 (DMSO) 重新平衡了UPR信号,提供了一个潜在的治疗策略.
科学领域:
- 毒理学 毒理学 毒理学
- 细胞生物学 细胞生物学
- 生物化学 生物化学
背景情况:
- 2-乙醇 (2CE) 是一种有毒代谢物,与急性肝损伤有关.
- 2CE诱导的肝毒性背后的精确机制尚未完全理解.
- 细胞内膜网膜 (ER) 应激和未展开的蛋白质反应 (UPR) 是关键的细胞防御途径.
研究的目的:
- 调查ER稳态和UPR信号在2CE诱导的肝损伤中的作用.
- 为了确定2CE毒性的潜在治疗干预措施.
主要方法:
- 对小鼠肝脏和H4IIEC3肝瘤细胞暴露于2CE.
- 对UPR信号通路 (IRE1α-XBP1s,PERK-eIF2α-CHOP,ATF6) 的分析.
- 用包括DMSO在内的各种调节剂评估细胞活力和体内毒性 (LD50).
- 使用4μ8C的药理抑制IRE1α.
主要成果:
- 2CE 破坏了 ER 稳态,并在体外激活了所有三个规范的 UPR 分支,在体内主要是 eIF2α-CHOP 信号.
- 在小鼠中,二甲基硫氧化物 (DMSO) 治疗改善了细胞活力,并增加了2CE的24小时LD50.
- DMSO通过维持XBP1s和减少亲细胞亡标记物来重新平衡UPR信号.
- 抑制 IRE1α 消除了 DMSO 的保护作用,并加剧了细胞死亡.
结论:
- UPR信号传递动态是2CE诱导的ER压力和随后的肝损伤的核心.
- IRE1α-XBP1s轴对2CE毒性起着关键的细胞保护作用.
- 向IRE1α-XBP1s通路代表了对2CE诱导的肝损伤的有希望的治疗策略.
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