Li Zhijie, Wang Heming, Zhu Junjin, Nan Ning, Lin Yi, Zhuang Xuran, Li Ling, Zhang Yamin, Huang Pengyu
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Cell Death Discov. 2022 Jul 19;8(1):328. doi: 10.1038/s41420-022-01123-0.
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.
急性肝衰竭（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，在无基础肝病的患者中死亡率很高。目前，ALF的有效治疗仅限于肝移植，这凸显了对新的靶向治疗的需求。在此，我们发现，在硫代乙酰胺（TAA）或对乙酰氨基酚（APAP）诱导的ALF过程中，肝脏肿瘤坏死因子样凋亡弱诱导剂（TWEAK）及其受体肿瘤坏死因子受体超家族成员12A（Tnfrsf12a）的表达显著增加。抑制TWEAK/Tnfrsf12a轴可显著减轻TAA或APAP诱导的ALF。此外，我们的结果表明，TWEAK/Tnfrsf12a轴诱导肝细胞发生受体相互作用蛋白激酶1（RIPK1）依赖性凋亡，而非坏死性凋亡或炎性小体介导的细胞焦亡。值得注意的是，ALF患者肝活检中肝脏TNFRSF12A和TWEAK水平也显著升高。总之，我们的结果表明，在ALF期间，TWEAK/Tnfrsf12a轴激活肝细胞中的RIPK1，导致RIPK1依赖性凋亡及随后的肝损伤。因此，抑制TWEAK/Tnfrsf12a轴或RIPK1依赖性凋亡可减轻肝损伤，为ALF的治疗提供了一个新的潜在治疗靶点。
