甲基四氢叶酸还原酶2在恶性肿瘤中代谢的研究进展
Research Progress on MTHFD2 in Malignant Tumors
DOI: 10.12677/acm.2025.152479, PDF,    科研立项经费支持
作者: 韦世鑫, 冯 成, 叶自钊：右江民族医学院附属西南医院，广西 百色；百色市人民医院耳鼻咽喉头颈外科，广西 百色；杨开炎, 韦福依*：右江民族医学院附属西南医院，广西 百色
关键词: MTHFD2；恶性肿瘤；一碳代谢；代谢重编程；MTHFD2； Malignant Tumor； One-Carbon Metabolism； Metabolic Reprogramming
摘要: 亚甲基四氢叶酸还原酶2 (Methylenetetrahydrofolate dehydrogenase 2, MTHFD2)是一种参与叶酸代谢的四甲基叶酸脱氢酶，主要位于线粒体内，在一碳代谢过程中催化亚甲基四氢叶酸成甲酰基四氢叶酸。MTHFD2在恶性肿瘤组织中表达上调，在正常组织中几乎不表达，在肿瘤代谢重编程中发挥重要作用，通过AKT、JAK/STAT等信号通路调控代谢，影响细胞一碳代谢、有氧糖酵解，以适应快速增值的细胞所需要的物质，多数证据都表明其与肿瘤的发生、预后有着密切的关系，并将其作为预后标志物或潜在的治疗靶点。目前MTHFD2在人类恶性肿瘤中的代谢作用机制尚未明确，未来深入研究MTHFD2在肿瘤代谢重编程与信号通路的关系及其作为肿瘤治疗靶标的作用，可为恶性肿瘤的治疗提供新决策。
Abstract: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is an enzyme involved in folate metabolism, primarily located in the mitochondria. It catalyzes the conversion of methylenetetrahydrofolate to formyltetrahydrofolate during one-carbon metabolism. MTHFD2 is upregulated in malignant tumors and is almost not expressed in normal tissues, playing a significant role in tumor metabolic reprogramming. It regulates metabolism through signaling pathways such as AKT and JAK/STAT, affecting cellular one-carbon metabolism and aerobic glycolysis to accommodate the needs of rapidly proliferating cells. Most evidence suggests a close relationship between MTHFD2 expression and tumor development and prognosis, making it a potential prognostic marker or therapeutic target. Currently, the mechanisms of MTHFD2’s metabolic roles in human malignancies are not well understood. Future in-depth studies on the relationship between MTHFD2 in tumor metabolic reprogramming and signaling pathways, and its role as a therapeutic target, could provide new decisions for the treatment of malignant tumors.
文章引用：韦世鑫, 冯成, 叶自钊, 杨开炎, 韦福依. 甲基四氢叶酸还原酶2在恶性肿瘤中代谢的研究进展[J]. 临床医学进展, 2025, 15(2): 1324-1331. https://doi.org/10.12677/acm.2025.152479

参考文献

[1] Mattiuzzi, C. and Lippi, G. (2019) Current Cancer Epidemiology. Journal of Epidemiology and Global Health, 9, 217-222. [Google Scholar] [CrossRef] [PubMed]
[2] Nicolaidou, V., Papaneophytou, C. and Koufaris, C. (2020) Detection and Characterisation of Novel Alternative Splicing Variants of the Mitochondrial Folate Enzyme MTHFD2. Molecular Biology Reports, 47, 7089-7096. [Google Scholar] [CrossRef] [PubMed]
[3] Zhao, L.N. and Kaldis, P. (2022) The Catalytic Mechanism of the Mitochondrial Methylenetetrahydrofolate Dehydrogenase/Cyclohydrolase (MTHFD2). PLOS Computational Biology, 18, e1010140. [Google Scholar] [CrossRef] [PubMed]
[4] Scaletti, E.R., Gustafsson Westergren, R., Andersson, Y., Wiita, E., Henriksson, M., Homan, E.J., et al. (2022) The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform‐Selective Inhibitors. ChemMedChem, 17, e202200274. [Google Scholar] [CrossRef] [PubMed]
[5] Wei, Y., Liu, P., Li, Q., Du, J., Chen, Y., Wang, Y., et al. (2019) The Effect of MTHFD2 on the Proliferation and Migration of Colorectal Cancer Cell Lines. OncoTargets and Therapy, 12, 6361-6370. [Google Scholar] [CrossRef] [PubMed]
[6] Rather, G.M. (2023) Folate Trapping Is Lethal to Cancer Cells. Chemical Biology & Drug Design, 102, 1588-1591. [Google Scholar] [CrossRef] [PubMed]
[7] Tedeschi, P.M., Vazquez, A., Kerrigan, J.E. and Bertino, J.R. (2015) Mitochondrial Methylenetetrahydrofolate Dehydrogenase (MTHFD2) Overexpression Is Associated with Tumor Cell Proliferation and Is a Novel Target for Drug Development. Molecular Cancer Research, 13, 1361-1366. [Google Scholar] [CrossRef] [PubMed]
[8] Zhu, L., Liu, X., Zhang, W., Hu, H., Wang, Q. and Xu, K. (2022) MTHFD2 Is a Potential Oncogene for Its Strong Association with Poor Prognosis and High Level of Immune Infiltrates in Urothelial Carcinomas of Bladder. BMC Cancer, 22, Article No. 556. [Google Scholar] [CrossRef] [PubMed]
[9] Sun, B., He, Z., Liu, G., Fu, X., Chen, Z. and Li, G. (2021) Methylene Tetrahydrofolate Dehydrogenase 2 (MTHFD2) Is Overexpressed in Head and Neck Squamous Cell Carcinoma (HNSCC) and Correlated with Patient’s Poor Prognosis. Pteridines, 32, 98-105. [Google Scholar] [CrossRef] 
[10] Liu, X., Huang, Y., Jiang, C., Ou, H., Guo, B., Liao, H., et al. (2016) Methylenetetrahydrofolate Dehydrogenase 2 Overexpression Is Associated with Tumor Aggressiveness and Poor Prognosis in Hepatocellular Carcinoma. Digestive and Liver Disease, 48, 953-960. [Google Scholar] [CrossRef] [PubMed]
[11] He, H., Li, P., Jia, W., Hu, B. and Ji, C. (2020) High Expression of Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) in Esophageal Squamous Cell Carcinoma and Its Clinical Prognostic Significance. Medical Science Monitor, 26, e920259. [Google Scholar] [CrossRef] [PubMed]
[12] Arslan, R. and Ceylan, O. (2022) MTHFD2 Expression Profile and Its Prognostic Importance in Invasive Breast Carcinoma. International Journal of Medical Science and Clinical Invention, 9, 6014-5922. [Google Scholar] [CrossRef] 
[13] Shi, L., Zhang, Q., Shou, X. and Niu, H. (2021) Expression and Prognostic Value Identification of Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) in Brain Low-Grade Glioma. International Journal of General Medicine, 14, 4517-4527. [Google Scholar] [CrossRef] [PubMed]
[14] Yao, S., Peng, L., Elakad, O., Küffer, S., Hinterthaner, M., Danner, B.C., et al. (2021) One Carbon Metabolism in Human Lung Cancer. Translational Lung Cancer Research, 10, 2523-2538. [Google Scholar] [CrossRef] [PubMed]
[15] Cui, X., Su, H., Yang, J., Wu, X., Huo, K., Jing, X., et al. (2022) Up-regulation of MTHFD2 Is Associated with Clinicopathological Characteristics and Poor Survival in Ovarian Cancer, Possibly by Regulating MOB1A Signaling. Journal of Ovarian Research, 15, Article No. 23. [Google Scholar] [CrossRef] [PubMed]
[16] Zhang, H., Zhu, S., Zhou, H., Li, R., Xia, X. and Xiong, H. (2023) Identification of MTHFD2 as a Prognostic Biomarker and Ferroptosis Regulator in Triple-Negative Breast Cancer. Frontiers in Oncology, 13, Article 1098357. [Google Scholar] [CrossRef] [PubMed]
[17] Cao, Y., Dai, Z., Xie, G., Liu, G., Guo, L. and Zhang, J. (2023) A Novel Metabolic-Related Gene Signature for Predicting Clinical Prognosis and Immune Microenvironment in Head and Neck Squamous Cell Carcinoma. Experimental Cell Research, 428, Article ID: 113628. [Google Scholar] [CrossRef] [PubMed]
[18] Boroughs, L.K. and DeBerardinis, R.J. (2015) Metabolic Pathways Promoting Cancer Cell Survival and Growth. Nature Cell Biology, 17, 351-359. [Google Scholar] [CrossRef] [PubMed]
[19] Wang, J., Yu, Z., Jiang, Y., Le, T., Wu, Y., Li, Z., et al. (2024) Downregulation of MTHFD2 Inhibits Proliferation and Enhances Chemosensitivity in Hepatocellular Carcinoma via PI3K/AKT Pathway. Frontiers in Bioscience-Landmark, 29, 35. [Google Scholar] [CrossRef] [PubMed]
[20] Huang, J., Qin, Y., Lin, C., Huang, X. and Zhang, F. (2021) MTHFD2 Facilitates Breast Cancer Cell Proliferation via the AKT Signaling Pathway. Experimental and Therapeutic Medicine, 22, Article No. 703. [Google Scholar] [CrossRef] [PubMed]
[21] Shi, Y., Xu, Y., Yao, J., Yan, C., Su, H., Zhang, X., et al. (2021) MTHFD2 Promotes Tumorigenesis and Metastasis in Lung Adenocarcinoma by Regulating AKT/GSK‐3β/β‐Catenin Signalling. Journal of Cellular and Molecular Medicine, 25, 7013-7027. [Google Scholar] [CrossRef] [PubMed]
[22] Li, Q., Yang, F., Shi, X., Bian, S., Shen, F., Wu, Y., et al. (2021) MTHFD2 Promotes Ovarian Cancer Growth and Metastasis via Activation of the STAT3 Signaling Pathway. FEBS Open Bio, 11, 2845-2857. [Google Scholar] [CrossRef] [PubMed]
[23] Deng, X., Liu, X., Hu, B., Liu, J., Fu, B. and Zhang, W. (2022) Upregulation of MTHFD2 Is Associated with PDL1 Activation in Bladder Cancer via the PI3K/AKT Pathway. International Journal of Molecular Medicine, 51, Article No. 14. [Google Scholar] [CrossRef] [PubMed]
[24] Wu, S., Cai, W., Shi, Z., Ming, X., Yang, X., Zhou, Y., et al. (2022) Knockdown of MTHFD2 Inhibits Proliferation and Migration of Nasopharyngeal Carcinoma Cells through the ERK Signaling Pathway. Biochemical and Biophysical Research Communications, 614, 47-55. [Google Scholar] [CrossRef] [PubMed]
[25] Mo, X., Liu, Q., Liang, K. and Song, Y. (2024) Interference with MTHFD2 Induces Ferroptosis in Ovarian Cancer Cells through ERK Signaling to Suppress Tumor Malignant Progression. Journal of Bioenergetics and Biomembranes, 56, 333-345. [Google Scholar] [CrossRef] [PubMed]
[26] Zhou, F., Yuan, Z., Gong, Y., Li, L., Wang, Y., Wang, X., et al. (2023) Pharmacological Targeting of MTHFD2 Suppresses NSCLC via the Regulation of ILK Signaling Pathway. Biomedicine & Pharmacotherapy, 161, Article ID: 114412. [Google Scholar] [CrossRef] [PubMed]
[27] Yue, L., Pei, Y., Zhong, L., Yang, H., Wang, Y., Zhang, W., et al. (2020) MTHFD2 Modulates Mitochondrial Function and DNA Repair to Maintain the Pluripotency of Mouse Stem Cells. Stem Cell Reports, 15, 529-545. [Google Scholar] [CrossRef] [PubMed]
[28] Liu, X., Liu, S., Piao, C., Zhang, Z., Zhang, X., Jiang, Y., et al. (2021) Non‐Metabolic Function of MTHFD2 Activates CDK2 in Bladder Cancer. Cancer Science, 112, 4909-4919. [Google Scholar] [CrossRef] [PubMed]
[29] Koufaris, C., Gallage, S., Yang, T., Lau, C., Valbuena, G.N. and Keun, H.C. (2016) Suppression of MTHFD2 in MCF-7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion. Journal of Proteome Research, 15, 2618-2625. [Google Scholar] [CrossRef] [PubMed]
[30] Ju, H., Lu, Y., Chen, D., Zuo, Z., Liu, Z., Wu, Q., et al. (2018) Modulation of Redox Homeostasis by Inhibition of MTHFD2 in Colorectal Cancer: Mechanisms and Therapeutic Implications. JNCI: Journal of the National Cancer Institute, 111, 584-596. [Google Scholar] [CrossRef] [PubMed]
[31] Cui, L., Chen, H. and Zhao, X. (2020) The Prognostic Significance of Immune-Related Metabolic Enzyme MTHFD2 in Head and Neck Squamous Cell Carcinoma. Diagnostics, 10, Article 689. [Google Scholar] [CrossRef] [PubMed]
[32] Wang, W., Gu, W., Tang, H., Mai, Z., Xiao, H., Zhao, J., et al. (2022) The Emerging Role of MTHFD Family Genes in Regulating the Tumor Immunity of Oral Squamous Cell Carcinoma. Journal of Oncology, 2022, Article ID: 4867730. [Google Scholar] [CrossRef] [PubMed]
[33] Green, N.H., Galvan, D.L., Badal, S.S., Chang, B.H., LeBleu, V.S., Long, J., et al. (2019) MTHFD2 Links RNA Methylation to Metabolic Reprogramming in Renal Cell Carcinoma. Oncogene, 38, 6211-6225. [Google Scholar] [CrossRef] [PubMed]
[34] Koufaris, C. and Nilsson, R. (2018) Protein Interaction and Functional Data Indicate MTHFD2 Involvement in RNA Processing and Translation. Cancer & Metabolism, 6, Article No. 12. [Google Scholar] [CrossRef] [PubMed]
[35] Shang, M., Ni, L., Shan, X., Cui, Y., Hu, P., Ji, Z., et al. (2023) MTHFD2 Reprograms Macrophage Polarization by Inhibiting PTEN. Cell Reports, 42, Article ID: 112481. [Google Scholar] [CrossRef] [PubMed]
[36] Shang, M., Yang, H., Yang, R., Chen, T., Fu, Y., Li, Y., et al. (2021) The Folate Cycle Enzyme MTHFD2 Induces Cancer Immune Evasion through PD-L1 Up-Regulation. Nature Communications, 12, Article No. 1940. [Google Scholar] [CrossRef] [PubMed]
[37] Sugiura, A., Andrejeva, G., Voss, K., Heintzman, D.R., Xu, X., Madden, M.Z., et al. (2022) MTHFD2 Is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function. Immunity, 55, 65-81.e9. [Google Scholar] [CrossRef] [PubMed]
[38] Shukla, K., Singh, N., Lewis, J.E., Tsang, A.W., Boothman, D.A., Kemp, M.L., et al. (2020) MTHFD2 Blockade Enhances the Efficacy of β-Lapachone Chemotherapy with Ionizing Radiation in Head and Neck Squamous Cell Cancer. Frontiers in Oncology, 10, Article 536377. [Google Scholar] [CrossRef] [PubMed]
[39] Zhao, R., Feng, T., Gao, L., Sun, F., Zhou, Q., Wang, X., et al. (2022) PPFIA4 Promotes Castration-Resistant Prostate Cancer by Enhancing Mitochondrial Metabolism through MTHFD2. Journal of Experimental & Clinical Cancer Research, 41, Article No. 125. [Google Scholar] [CrossRef] [PubMed]
[40] Pikman, Y., Puissant, A., Alexe, G., Furman, A., Chen, L.M., Frumm, S.M., et al. (2016) Targeting MTHFD2 in Acute Myeloid Leukemia. The Journal of Cell Biology, 214, 2141OIA135. [Google Scholar] [CrossRef] 
[41] Kawai, J., Ota, M., Ohki, H., Toki, T., Suzuki, M., Shimada, T., et al. (2019) Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold. ACS Medicinal Chemistry Letters, 10, 893-898. [Google Scholar] [CrossRef] [PubMed]

为你推荐