混合血统激酶域样蛋白 (MLKL) 被广泛认为是坏死样细胞死亡的执行者，在其中 MLKL 介导坏死样信号和触发细胞死亡，以一种依赖于受体相互作用蛋白激酶 3 (RIPK3) 的方式。近来，人们越来越注意到 RIPK3 在肝细胞中具有内在的沉默，这引起了关于 MLKL 在肝细胞癌 (HCC) 中的作用的问题。本研究报告了 MLKL 在调节与坏死样细胞死亡不同的编程性细胞死亡 - -“ parthanatos”中的以前未被认识的作用。在具有内在 RIPK3 缺陷的 HCC 细胞中，MLKL 的敲除阻碍了原位异种移植肿瘤生长，激活了抗肿瘤免疫应答，并增强了同种异体 HCC 肿瘤模型中免疫检查点阻断治疗的治疗效果。在机械学上，MLKL 在维持 HCC 细胞内质网 (ER)-线粒体 Mg2+ 动态方面是必需的。MLKL 缺乏限制了 ER Mg2+ 的释放和线粒体 Mg2+ 的摄取，导致 ER 功能障碍和线粒体氧化应激，这两者共同导致对代谢应激诱导的 parthanatos 的敏感性增加。重要的是，药理学上通过抑制聚腺苷酸核苷酸缀合酶阻止 parthanatos，可以恢复 MLKL 敲除 HCC 肿瘤中的肿瘤生长和免疫逃逸。综上所述，我们的数据证明了 MLKL 在调节 parthanatos 中的 RIPK3 无依赖性作用，并强调了 MLKL 在促进肝细胞癌中的免疫逃避中的作用。 © 2023。作者。

Mixed lineage kinase domain-like (MLKL) is widely accepted as an executioner of necroptosis, in which MLKL mediates necroptotic signaling and triggers cell death in a receptor-interacting protein kinase 3 (RIPK3)-dependent manner. Recently, it is increasingly noted that RIPK3 is intrinsically silenced in hepatocytes, raising a question about the role of MLKL in hepatocellular carcinoma (HCC). This study reports a previously unrecognized role of MLKL in regulating parthanatos, a programmed cell death distinct from necroptosis. In HCC cells with intrinsic RIPK3 deficiency, knockout of MLKL impedes the orthotopic tumor growth, activates the anti-tumor immune response and enhances the therapeutic effect of immune checkpoint blockade in syngeneic HCC tumor models. Mechanistically, MLKL is required for maintaining the endoplasmic reticulum (ER)-mitochondrial Mg2+ dynamics in HCC cells. MLKL deficiency restricts ER Mg2+ release and mitochondrial Mg2+ uptake, leading to ER dysfunction and mitochondrial oxidative stress, which together confer increased susceptibility to metabolic stress-induced parthanatos. Importantly, pharmacological inhibition of poly(ADP-ribose) polymerase to block parthanatos restores the tumor growth and immune evasion in MLKL-knockout HCC tumors. Together, our data demonstrate a new RIPK3-independent role of MLKL in regulating parthanatos and highlight the role of MLKL in facilitating immune evasion in HCC.© 2023. The Author(s).