假激酶混合谱系激酶结构域样 (MLK​​L) 是坏死性凋亡途径激活的重要组成部分。新的证据表明 MLKL 在肝脏疾病中发挥着关键作用。然而，MLKL 如何促进肝癌发生尚未完全阐明。在此，我们报告 MLKL 在二乙基亚硝胺 (DEN) 诱导的小鼠 HCC 模型中上调，并且与人类肝细胞癌相关。肝细胞特异性 MLKL 敲除可抑制肝癌发生的进展。相反，MLKL 过度表达会加剧 DEN 诱导的 HCC 的发生和进展。机制研究表明，MLKL 的缺失显着增加了自噬的激活，从而预防肝癌的发生。 MLKL 直接与 AMPKα1 相互作用并抑制其活性，独立于其坏死性凋亡功能。从机制上讲，MLKL 作为 AMPKα1 和蛋白磷酸酶 1B (PPM1B) 之间的桥接分子，从而增强 AMPKα1 的去磷酸化。一致地，HCC 患者中 MLKL 表达与 AMPKα1 磷酸化呈负相关。总而言之，我们的研究结果强调 MLKL 作为一种新型 AMPK 守门者，在抑制自噬和驱动肝癌发生中发挥关键作用，表明 MLKL-AMPKα1 轴是 HCC 的潜在治疗靶点。© 2024。作者，拥有独家许可ADMC 细胞差异与死亡协会。

The pseudokinase mixed lineage kinase domain-like (MLKL) is an essential component of the activation of the necroptotic pathway. Emerging evidence suggests that MLKL plays a key role in liver disease. However, how MLKL contributes to hepatocarcinogenesis has not been fully elucidated. Herein, we report that MLKL is upregulated in a diethylnitrosamine (DEN)-induced murine HCC model and is associated with human hepatocellular carcinomas. Hepatocyte-specific MLKL knockout suppresses the progression of hepatocarcinogenesis. Conversely, MLKL overexpression aggravates the initiation and progression of DEN-induced HCC. Mechanistic study reveals that deletion of MLKL significantly increases the activation of autophagy, thereby protecting against hepatocarcinogenesis. MLKL directly interacts with AMPKα1 and inhibits its activity independent of its necroptotic function. Mechanistically, MLKL serves as a bridging molecule between AMPKα1 and protein phosphatase 1B (PPM1B), thus enhancing the dephosphorylation of AMPKα1. Consistently, MLKL expression correlates negatively with AMPKα1 phosphorylation in HCC patients. Taken together, our findings highlight MLKL as a novel AMPK gatekeeper that plays key roles in inhibiting autophagy and driving hepatocarcinogenesis, suggesting that the MLKL-AMPKα1 axis is a potential therapeutic target for HCC.© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.