Mixed lineage kinase domain-like protein (MLKL) plays an important role in necroptosis, but the role and mechanism of MLKL in intestinal tumorigenesis remain unclear. Here, we found that hematopoietic- and nonhematopoietic-derived MLKL affected intestinal inflammation, but nonhematopoietic-derived MLKL primarily inhibited intestinal tumorigenesis. Loss of MLKL enhanced intestinal regeneration and the susceptibility to intestinal tumorigenesis in Apc^min/+ mice by hyperactivating the Janus kinase 2 (JAK2)/ signal transducer and activator of transcription 3 (STAT3) axis. Furthermore, MLKL deficiency increased interleukin-6 (IL-6) production in dendritic cells. Administration of anti-IL-6R antibody therapy reduced intestinal tumorigenesis in Apc^min/+Mlkl^-/- mice. Notably, low MLKL expression in human colorectal tumors, which enhanced STAT3 activation, was associated with decreased overall survival. Together, our results reveal that MLKL exhibits a suppressive effect during intestinal tumorigenesis by suppressing the IL-6/JAK2/STAT3 signals.

中文翻译：

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MLKL通过抑制STAT3信号通路抑制肠道肿瘤发生

混合谱系激酶结构域样蛋白（MLKL）在坏死性凋亡中起重要作用，但MLKL在肠道肿瘤发生中的作用和机制尚不清楚。在这里，我们发现造血和非造血来源的 MLKL 影响肠道炎症，但非造血来源的 MLKL 主要抑制肠道肿瘤发生。MLKL 的缺失通过过度激活 Janus 激酶 2 (JAK2)/信号转导和转录激活因子 3 (STAT3) 轴，增强了Apc ^{min/+小鼠的肠道再生和肠道肿瘤发生的易感性。}此外，MLKL 缺乏会增加树突状细胞中白细胞介素 6 (IL-6) 的产生。施用抗IL-6R抗体疗法可减少Apc ^min/+ Mlk1中的肠肿瘤发生^-/-老鼠。值得注意的是，人类结直肠肿瘤中 MLKL 的低表达增强了 STAT3 的激活，与总生存期降低有关。总之，我们的结果表明，MLKL 通过抑制 IL-6/JAK2/STAT3 信号在肠道肿瘤发生过程中表现出抑制作用。