RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis.
Lei WuXiao ZhangLu ZhengHuakan ZhaoGuifang YanQi ZhangYu ZhouJuan LeiJiangang ZhangJingchun WangRong XinLu JiangJin PengQian ChenSin Man LamGuanghou ShuiHongming MiaoYongsheng LiPublished in: Cancer immunology research (2020)
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.
Keyphrases
- fatty acid
- protein kinase
- reactive oxygen species
- insulin resistance
- cell death
- cell proliferation
- poor prognosis
- cancer therapy
- adipose tissue
- signaling pathway
- metabolic syndrome
- high glucose
- induced apoptosis
- risk assessment
- skeletal muscle
- oxidative stress
- climate change
- drug delivery
- drug induced
- endothelial cells