Metabolic reprogramming is critical for the polarization and function of tumor-associated macrophages (TAM) and hepatocarcinogenesis, but how this reprogramming occurs is unknown. Here, we showed that receptor-interacting protein kinase 3 (RIPK3), a central factor in necroptosis, is downregulated in hepatocellular carcinoma (HCC)-associated macrophages, which correlated with tumorigenesis and enhanced the accumulation and polarization of M2 TAMs. Mechanistically, RIPK3 deficiency in TAMs reduced reactive oxygen species and significantly inhibited caspase1-mediated cleavage of PPAR. These effects enabled PPAR activation and facilitated fatty acid metabolism, including fatty acid oxidation (FAO), and induced M2 polarization in the tumor microenvironment. RIPK3 upregulation or FAO blockade reversed the immunosuppressive activity of TAMs and dampened HCC tumorigenesis. Our findings provide molecular basis for the regulation of RIPK3-mediated, lipid metabolic reprogramming of TAMs, thus highlighting a potential strategy for targeting the immunometabolism of HCC.

中文翻译：

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RIPK3协调肿瘤相关巨噬细胞中的脂肪酸代谢和肝癌发生。

代谢重编程对于肿瘤相关巨噬细胞（TAM）的极化和功能以及肝癌的发生至关重要，但是这种重编程如何发生尚不清楚。在这里，我们显示，在肝细胞癌（HCC）相关的巨噬细胞中，与受体相互作用的蛋白激酶3（RIPK3）是坏死病的中心因子，其表达下调，这与肿瘤发生有关，并增强了M2 TAM的积累和极化。从机理上讲，TAM中的RIPK3缺乏会减少活性氧，并显着抑制caspase1介导的PPAR裂解。这些作用使PPAR活化并促进脂肪酸代谢，包括脂肪酸氧化（FAO），并在肿瘤微环境中诱导M2极化。RIPK3上调或FAO阻断逆转了TAMs的免疫抑制活性并抑制了HCC的肿瘤发生。我们的发现为调节RIPK3介导的TAM的脂质代谢重编程提供了分子基础，从而突显了靶向HCC免疫代谢的潜在策略。