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.

中文翻译：

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Selonsertib，一种通过ASK1–JNK–DRP1途径拯救巨噬细胞线粒体功能障碍而用于肝衰竭治疗的潜在药物

急性肝衰竭（ALF）与高死亡率相关，除肝移植和人工肝疗法外，尚无有效的治疗方法。这项研究旨在确定selonertib（ASK1的选择性抑制剂）对ALF治疗的作用，治疗范围和机制。脂多糖和d-半乳糖胺（LPS / GalN）用于模拟ALF。我们发现，selonsertib预处理可以显着改善ALF，这可以通过减少肝坏死和血清丙氨酸氨基转移酶，天冬氨酸氨基转移酶和炎性细胞因子水平来确定。然而，selonsertib仅在LPS / GalN给药后早期有效，并且治疗窗口有限与JNK和DRP1的激活和线粒体易位有关。进一步的实验表明，selonsertib可以通过评估巨噬细胞的线粒体膜电位和线粒体通透性转变孔的开放来减轻LPS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释放炎性细胞因子，这一点已通过使用mdivi（一种特定的DRP1抑制剂）得到证实。Selonsertib通过减弱JNK介导的DRP1线粒体易位，然后挽救巨噬细胞中的线粒体损伤，从而保护其免受LPS / GalN诱导的ALF的侵害，并且可能对早期ALF患者具有治疗潜力。Selonsertib还通过减少DRP1介导的线粒体功能障碍来抑制巨噬细胞释放炎性细胞因子，这一点已通过使用mdivi（一种特定的DRP1抑制剂）得到证实。Selonsertib通过减弱JNK介导的DRP1线粒体易位，然后挽救巨噬细胞中的线粒体损伤，从而保护其免受LPS / GalN诱导的ALF的侵害，并且可能对早期ALF患者具有治疗潜力。Selonsertib还通过减少DRP1介导的线粒体功能障碍来抑制巨噬细胞释放炎性细胞因子，这一点已通过使用mdivi（一种特定的DRP1抑制剂）得到证实。Selonsertib通过减弱JNK介导的DRP1线粒体易位，然后挽救巨噬细胞中的线粒体损伤，从而保护其免受LPS / GalN诱导的ALF的侵害，并且可能对早期ALF患者具有治疗潜力。