RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis
RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis
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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
DOI：
10.1158/2326-6066.cir-19-0261
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发表时间：
2020-05-01
影响因子：
10.1
通讯作者：
Li, Yongsheng
中科院分区：
文献类型：
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作者：
Wu, Lei;Zhang, Xiao;Li, Yongsheng
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发生至关重要，但这种重编程如何发生尚不清楚。在这里，我们发现，受体相互作用蛋白激酶3（RIPK3），在坏死性凋亡的核心因素，下调肝细胞癌（HCC）相关的巨噬细胞，这与肿瘤的发生和增强的积累和极化的M2 TAMs。从机制上讲，TAMs中RIPK3的缺乏减少了活性氧，并显著抑制了caspase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），并诱导肿瘤微环境中的M2极化。RIPK3上调或FAO阻断逆转了TAM的免疫抑制活性并抑制了HCC肿瘤发生。我们的研究结果为RIPK3介导的TAMs脂质代谢重编程的调控提供了分子基础，从而突出了针对HCC免疫代谢的潜在策略。
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 caspasel-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.