Selonsertib, a potential drug for liver failure therapy by rescuing the mitochondrial dysfunction of macrophage via ASK1-JNK-DRP1 pathway.
Selonsertib, a potential drug for liver failure therapy by rescuing the mitochondrial dysfunction of macrophage via ASK1-JNK-DRP1 pathway.
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Selonsertib，一种通过 ASK1–JNK–DRP1 途径挽救巨噬细胞线粒体功能障碍来治疗肝衰竭的潜在药物
DOI：
10.1186/s13578-020-00525-w
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发表时间：
2021-01-07
影响因子：
7.5
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Lou G;Li A;Cen Y;Yang Q;Zhang T;Qi J;Chen Z;Liu Y
急性肝功能衰竭(ALF)死亡率高，除肝移植和人工肝治疗外，目前尚无有效的治疗方法。本研究旨在探讨ASK1的选择性抑制剂塞隆昔布治疗ALF的疗效、治疗窗及作用机制。用脂多糖和D-氨基半乳糖(LPS/GalN)模拟ALF。我们发现，塞隆昔布可显著改善ALF，其结果是肝坏死减少，血清丙氨酸氨基转移酶、天冬氨酸转氨酶和炎症细胞因子水平降低。然而，Selonsertib仅在内毒素/GalN给药后早期起作用，有限的治疗窗口与JNK和Drp1的激活和线粒体易位有关。进一步的实验表明，Seonsertib可以通过评估巨噬细胞线粒体膜电位和线粒体通透性转换孔的开放程度来减轻内毒素诱导的巨噬细胞线粒体损伤。Selonsertib还通过减少Drp1介导的线粒体功能障碍来抑制巨噬细胞的炎性细胞因子的释放，这一点通过使用特异性Drp1抑制剂mdivi得到了证实。Selonsertib通过减轻JNK介导的Drp1线粒体易位，从而保护巨噬细胞线粒体损伤，对早期ALF患者有治疗潜力。
Acute liver failure (ALF) is associated with a high mortality rate, and there are still no effective treatments except liver transplantation and artificial liver therapies. This study aimed to determine the effects, therapeutic window and mechanisms of selonsertib, a selective inhibitor of ASK1, for ALF therapy. Lipopolysaccharide and d-galactosamine (LPS/GalN) were used to simulate ALF. We found that selonsertib pretreatment significantly ameliorated ALF, as determined by reduced hepatic necrosis and serum alanine aminotransferase, aspartate aminotransferase and inflammatory cytokine levels. However, selonsertib is only effective early after LPS/GalN administration, and the limited therapeutic window is related to the activation and mitochondrial translocation of JNK and DRP1. Further experiments revealed that selonsertib could alleviate LPS-induced mitochondrial damage in macrophages by evaluating the mitochondrial membrane potential and mitochondrial permeability transition pore opening in macrophages. Selonsertib also suppressed the release of inflammatory cytokines from macrophages by reducing DRP1-mediated mitochondrial dysfunction, which was confirmed by using mdivi, a specific DRP1 inhibitor. Selonsertib protected against LPS/GalN-induced ALF by attenuating JNK-mediated DRP1 mitochondrial translocation and then rescuing mitochondrial damage in macrophages and may have therapeutic potential for early ALF patients.
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影响因子：
30.5
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