Inhibition of TWEAK/Tnfrsf12a axis protects against acute liver failure by suppressing RIPK1-dependent apoptosis.
Inhibition of TWEAK/Tnfrsf12a axis protects against acute liver failure by suppressing RIPK1-dependent apoptosis.
复制标题
抑制TWEAK/Tnfrsf12a轴通过抑制ripk1依赖性细胞凋亡来保护急性肝衰竭。
DOI：
10.1038/s41420-022-01123-0
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发表时间：
2022-07-19
影响因子：
7
通讯作者：
Huang, Pengyu
中科院分区：
文献类型：
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作者：
Li, Zhijie;Wang, Heming;Zhu, Junjin;Nan, Ning;Lin, Yi;Zhuang, Xuran;Li, Ling;Zhang, Yamin;Huang, Pengyu
急性肝功能衰竭（Acute liver failure，ALF）是一种严重的临床综合征，其特征是肝细胞在短时间内大量死亡，导致凝血功能障碍和肝性脑病，在既往无肝病的患者中死亡率很高。ALF的有效治疗目前仅限于肝移植，突出了对新靶向治疗的需求。本研究发现，在硫代乙酰胺（TAA）或对乙酰氨基酚（APAP）诱导的ALF过程中，肝肿瘤坏死因子样弱凋亡诱导因子（TWEAK）及其受体肿瘤坏死因子受体超家族成员12 A（Tnfrsf 12 a）的表达显著增加。抑制TWEAK/Tnfrsf 12 a轴显著减弱TAA或APAP诱导的ALF。此外，我们的研究结果表明，TWEAK/Tnfrsf 12 a轴诱导受体相互作用蛋白激酶1（RIPK 1）依赖性肝细胞凋亡，而不是坏死性凋亡或焦亡。值得注意的是，在来自ALF患者的肝活检中，肝TNFRSF 12 A和TWEAK水平也显著增加。总之，我们的研究结果表明，在ALF期间，TWEAK/Tnfrsf 12 a轴激活肝细胞中的RIPK 1，导致RIPK 1依赖性细胞凋亡和随后的肝损伤。因此，抑制TWEAK/Tnfrsf 12 a轴或RIPK 1依赖性细胞凋亡可减轻肝损伤，为治疗ALF提供了新的潜在治疗靶点。
Acute liver failure (ALF) is a severe clinical syndrome characterized by massive death of hepatocytes in a short time, resulting in coagulopathy and hepatic encephalopathy, with a high mortality in patients without pre-existing liver disease. Effective treatment of ALF is currently limited to liver transplantation, highlighting the need for new target therapies. Here, we found that expression of hepatic tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor tumor necrosis factor receptor superfamily member 12A (Tnfrsf12a) were significantly increased during ALF induced by thioacetamide (TAA) or acetaminophen (APAP). Inhibition of TWEAK/Tnfrsf12a axis markedly attenuated TAA or APAP-induced ALF. Moreover, our results demonstrated that TWEAK/Tnfrsf12a axis induced receptor-interacting protein kinase 1 (RIPK1)-dependent apoptosis of hepatocytes, instead of necroptosis or pyroptosis. Notably, hepatic TNFRSF12A and TWEAK levels were also significantly increased in liver biopsies from ALF patients. In summary, our results demonstrate that during ALF, TWEAK/Tnfrsf12a axis activates RIPK1 in hepatocytes, leading to RIPK1-dependent apoptosis and subsequent liver injury. Therefore, inhibition of either TWEAK/Tnfrsf12a axis or RIPK1-dependent apoptosis attenuates liver injury, providing a new potential therapeutic target for the treatment of ALF.
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DOI：
10.1007/s10495-008-0187-8
发表时间：
2008-04
期刊：
Apoptosis : an international journal on programmed cell death
影响因子：
--
作者：
Silva MT;do Vale A;dos Santos NM
通讯作者：
dos Santos NM
影响因子：
64.8
作者：
Shi, Jianjin;Zhao, Yue;Shao, Feng
通讯作者：
Shao, Feng
影响因子：
4.1
作者：
Slee, EA;Zhu, HJ;Cohen, GM
通讯作者：
Cohen, GM
影响因子：
3.3
作者：
Desplat-Jégo, S;Varriale, S;Boucraut, J
通讯作者：
Boucraut, J
影响因子：
7
作者：
通讯作者：
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