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.

中文翻译：

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多物种转录组学将 SIKE 确定为 MAPK 阻遏蛋白，可预防 NASH 进展

非酒精性脂肪肝 (NAFL) 仍然相对良性，但当其发展为非酒精性脂肪性肝炎 (NASH) 时，终末期肝病的高风险变得非常普遍。我们目前对 NAFL 向 NASH 发展的了解仍然不足。在这项研究中，我们发现 MAP 激酶 (MAPK) 激活是与多个物种的 NASH 进展相关的最显着的分子特征。此外，我们还发现了 IKKε 的抑制因子（思克）作为 MAPK 激活的保守且有效的负控制器。肝细胞特异性过度表达司克在饮食和毒素诱导的小鼠 NASH 模型中阻止 NASH 进展。从机制上讲，SIKE 直接与 TGF-β 激活激酶 1 (TAK1) 和 TAK1 结合蛋白 2 (TAB2) 相互作用，以中断它们的结合以及随后的 TAK1-MAPK 信号传导激活。我们发现吲哚布芬显着上调思克表达并有效改善小鼠和猕猴的 NASH 特征。这些发现将 SIKE 确定为一种 MAPK 抑制剂，可预防 NASH 进展，并为靶向 SIKE-TAK1 轴作为潜在的 NASH 治疗提供概念验证证据。