Emerging Role of ACOD1/Itaconate in Cancer:Bridging Metabolic Reprogramming and Signaling in the Tumor MicroenvironmentOA
Itaconate,produced by aconitate decarboxylase 1(ACOD1,also known as IRG1),acts as a key immunometabolite that inhibits succinate dehydrogenase(SDH)and can engage reduction-oxidation(redox)-sensitive signaling programs.This review summarizes the emerging,context-dependent roles of the ACOD1-itaconate axis in cancer,while critically distinguishing between the effects of endogenous itaconate and its cell-permeable derivatives.In tumor cells,endogenous ACOD1 expression or uptake via solute carrier family 13 member 3(SLC13A3)alters oxidative phosphorylation and glycolysis.In the tumor microenvironment,myeloid-derived itaconate contributes to immune tolerance by reducing dendritic-cell cross-priming and limiting CD8^(+)T-cell metabolic activity.Moreover,interactions between ACOD1-derived endogenous itaconate and stress-responsive signaling pathways,including Extracellular Signal-Regulated Kinase(ERK)1/2 and AMP-activated Protein Kinase(AMPK),couple mitochondrial metabolic perturbation to adaptive cellular responses,whereas electrophilic itaconate derivatives can additionally engage ERK-and Nuclear Factor Erythroid 2-related factor 2(NRF2)-linked cytoprotective programs.Collectively,these findings highlight the ACOD1/itaconate axis as a context-dependent node of metabolic control,offering new perspectives for a stratified therapeutic approach based on tumor lineage and transporter expression.
Xing-Guo Li;Lu-Kai Wang;Fu-Ming Tsai;Hsueh-Chun Wang
Graduate Institute of Biomedical Sciences,College of Medicine,China Medical University,Taichung,Taiwan,China Research Center for Cancer Biology,China Medical University,Taichung,Taiwan,China Institute of Biochemistry and Molecular Biology,College of Life Sciences,China Medical University,Taichung,Taiwan,ChinaNational Center for Biomodels,National Institutes of Applied Research,Taipei,Taiwan,ChinaDepartment of Research,Taipei Tzu Chi Hospital,Buddhist Tzu Chi Medical Foundation,New Taipei City,Taiwan,ChinaGraduate Institute of Biomedical Sciences,College of Medicine,China Medical University,Taichung,Taiwan,China
医药卫生
Aconitate decarboxylase 1AMP-activated protein kinaseitaconatecancerextracellular signalregulated kinasemitochondrial metabolismnuclear factor erythroid 2-related factor 2reduction-oxidation signaling
《BIOCELL》 2026 (6)
P.91-107,17
supported by China Medical University,Taiwan(CMU112-MF-31,CMU112-S-52,CMU113-S-57 to HCW,and CMU109-YT-03 to XGL)supported by the Cancer Biology and Precision Therapeutics Center,China Medical University,from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project。
评论