转录组
抑制因子
MAPK/ERK通路
细胞生物学
生物
化学
基因
计算生物学
基因表达
磷酸化
生物化学
作者
Lan Bai,Weiyi Qu,Xu Cheng,Hailong Yang,Yongping Huang,Zhenya Wang,Cuijuan Han,Ruifeng Tian,Fengjiao Hu,Ling Yang,Song Tian,Han Tian,Zhiwei Cai,Juan Wan,Jingwei Jiang,Jiajun Fu,Junjie Zhou,Yufeng Hu,Tengfei Ma,Xin Zhang
标识
DOI:10.1126/scitranslmed.ade7347
摘要
Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε ( SIKE ) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of Sike prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-β–activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated SIKE expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.
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