Direct Inhibition of GSDMD by PEITC Reduces Hepatocyte Pyroptosis and Alleviates Acute Liver Injury in Mice.
Direct Inhibition of GSDMD by PEITC Reduces Hepatocyte Pyroptosis and Alleviates Acute Liver Injury in Mice.
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PEITC 直接抑制 GSDMD 可减少小鼠肝细胞焦亡并减轻急性肝损伤。
DOI：
10.3389/fimmu.2022.825428
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发表时间：
2022
影响因子：
7.3
通讯作者：
Xu Q
中科院分区：
文献类型：
--
作者：
Wang J;Shi K;An N;Li S;Bai M;Wu X;Shen Y;Du R;Cheng J;Wu X;Xu Q
急性肝损伤（Acute liver injury， ALI）是临床上最常见的肝脏疾病之一，常由病毒、酒精、药物等引起。虽然焦亡在ALI中起着重要作用，但目前仍缺乏与该机制相关的有效临床药物。在这里，我们发现异硫氰酸苯乙酯（PEITC），一种存在于十字花科蔬菜中的天然化合物，可以以剂量依赖的方式显著缓解豆豆素a （ConA）诱导的炎症性肝损伤和四氯化碳（CCl4）诱导的化学性肝损伤。PEITC剂量依赖性地逆转了li诱导的血浆天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、乳酸脱氢酶（LDH）、肿瘤坏死因子(TNF)-α和干扰素(IFN)-γ水平的升高，并降低了肝细胞焦亡标志物如nod样受体家族pyrin domain containing 3 （NLRP3）、cleaved caspase-1和cleaved gasdermin D （GSDMD）的蛋白水平。体外实验也证实了PEITC对肝细胞焦亡的抑制作用。此外，PEITC通过与GSDMD的半胱氨酸191相互作用来抑制焦亡。总之，我们的研究结果确定了PEITC通过直接抑制GSDMD来挽救肝细胞焦亡的作用，这可能为ALI提供一种新的潜在治疗策略。
Acute liver injury (ALI), often caused by viruses, alcohol, drugs, etc., is one of the most common clinical liver diseases. Although pyroptosis plays an important role in ALI, there is still a lack of effective clinical drugs related to this mechanism. Here, we show that phenethyl isothiocyanate (PEITC), a natural compound present in cruciferous vegetables, can significantly alleviate concanavalin A (ConA)-induced inflammatory liver damage and carbon tetrachloride (CCl4)-induced chemical liver damage in a dose-dependent manner. PEITC dose-dependently reversed the ALI-induced increase in plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and reduced the protein levels of hepatocyte pyroptosis markers such as Nod-like receptor family pyrin domain containing 3 (NLRP3), cleaved caspase-1, and cleaved gasdermin D (GSDMD). In vitro experiments have also verified the inhibitory effect of PEITC on hepatocyte pyroptosis. Furthermore, PEITC inhibits pyroptosis by interacting with cysteine 191 of GSDMD. In summary, our findings establish a role for PEITC in rescuing hepatocyte pyroptosis via direct inhibition of GSDMD, which may provide a new potential therapeutic strategy for ALI.