{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMTHFD2 is a mitochondrial enzyme that plays a central role in one‐carbon metabolism by providing essential one‐carbon units for nucleotide synthesis, methylation reactions, and redox homeostasis. This enzyme is normally expressed during embryonic development, but its re‐expression in many adult malignancies supports rapid tumor cell proliferation and survival. Elevated levels of MTHFD2 have been observed across a wide range of cancers—including breast, colorectal, acute myeloid leukemia and renal, among others—often correlating with poor prognosis and aggressive disease. In several studies, its overexpression has been linked to metabolic remodeling in cancer cells, such as the induction of a glycine auxotrophy in breast cancer and a shift toward purine biosynthesis in leukemic and endothelial models, highlighting its function as a key metabolic node."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical metabolic role, MTHFD2 exhibits non‐metabolic and regulatory functions that contribute to tumor progression. It has been implicated in maintaining genomic stability by modulating DNA repair processes such as nonhomologous end joining and by influencing replication fork dynamics, which can result in replication stress when perturbed. Moreover, MTHFD2 engages in “moonlighting” activities—such as interacting with key cell cycle regulators (for example, direct association with CDK2 in bladder cancer) and enhancing oncogenic signaling through pathways such as AKT/GSK‐3β/β‐catenin or STAT3 activation. Its expression is also regulated at multiple levels, including alternative splicing and post‐translational modifications, and is modulated by oncogenic drivers (like MYCN) and microRNAs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, MTHFD2 functions as an adaptive regulator and prognostic biomarker by modulating tumor cell “stemness,” drug resistance, and immune evasion. It influences the cellular response to nutrient stress—such as during glutamine deprivation or oxidative challenges—by linking metabolic flux to stress response pathways like the unfolded protein response. In some tumor types, disruption of MTHFD2 not only impairs metabolic homeostasis but also alters cell–cell signaling (for example, by promoting PD‐L1 expression via the PI3K/AKT pathway), thereby affecting the tumor microenvironment and response to therapy. Its dysregulated expression, sometimes mediated by upstream noncoding RNAs or genetic polymorphisms, has been associated with adverse clinical parameters in cancers ranging from glioblastoma and ovarian to endometrial, esophageal, and gastric carcinomas."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Gary M Shaw, Wei Lu, Huiping Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2350-10-49"}], "href": "https://doi.org/10.1186/1471-2350-10-49"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19493349"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19493349"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Laura Lehtinen, Kirsi Ketola, Rami Mäkelä, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High-throughput RNAi screening for novel modulators of vimentin expression identifies MTHFD2 as a regulator of breast cancer cell migration and invasion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.756"}], "href": "https://doi.org/10.18632/oncotarget.756"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23295955"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23295955"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Roland Nilsson, Mohit Jain, Nikhil Madhusudhan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms4128"}], "href": "https://doi.org/10.1038/ncomms4128"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24451681"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24451681"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Feng Liu, Yang Liu, Chuan He, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased MTHFD2 expression is associated with poor prognosis in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13277-014-2111-x"}], "href": "https://doi.org/10.1007/s13277-014-2111-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24870594"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24870594"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Nina Gustafsson Sheppard, Lisa Jarl, Diana Mahadessian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep15029"}], "href": "https://doi.org/10.1038/srep15029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26461067"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26461067"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xincheng Liu, Yu Huang, Chenglong Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Methylenetetrahydrofolate dehydrogenase 2 overexpression is associated with tumor aggressiveness and poor prognosis in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dig Liver Dis (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.dld.2016.04.015"}], "href": "https://doi.org/10.1016/j.dld.2016.04.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27257051"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27257051"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Costas Koufaris, Suchira Gallage, Tianlai Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Suppression of MTHFD2 in MCF-7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Proteome Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acs.jproteome.6b00188"}], "href": "https://doi.org/10.1021/acs.jproteome.6b00188"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27315223"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27315223"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yana Pikman, Alexandre Puissant, Gabriela Alexe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting MTHFD2 in acute myeloid leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20151574"}], "href": "https://doi.org/10.1084/jem.20151574"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27325891"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27325891"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Robert Gustafsson, Ann-Sofie Jemth, Nina M S Gustafsson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-16-1476"}], "href": "https://doi.org/10.1158/0008-5472.CAN-16-1476"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27899380"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27899380"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Yueli Gu, Jinchun Si, Xichun Xiao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-92a Inhibits Proliferation and Induces Apoptosis by Regulating Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) Expression in Acute Myeloid Leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3727/096504016X14829256525028"}], "href": "https://doi.org/10.3727/096504016X14829256525028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28059050"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28059050"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Juliane Hitzel, Eunjee Lee, Yi Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-018-04602-0"}], "href": "https://doi.org/10.1038/s41467-018-04602-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29895827"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29895827"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Hao Lin, Bin Huang, Hua Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MTHFD2 Overexpression Predicts Poor Prognosis in Renal Cell Carcinoma and is Associated with Cell Proliferation and Vimentin-Modulated Migration and Invasion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Physiol Biochem (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000495402"}], "href": "https://doi.org/10.1159/000495402"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30466107"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30466107"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Tatsunori Nishimura, Asuka Nakata, Xiaoxi Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-018-0589-1"}], "href": "https://doi.org/10.1038/s41388-018-0589-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30532069"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30532069"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Yan Yan, Ding Zhang, Ting Lei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-33a-5p suppresses colorectal cancer cell growth by inhibiting MTHFD2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Exp Pharmacol Physiol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/1440-1681.13125"}], "href": "https://doi.org/10.1111/1440-1681.13125"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31209892"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31209892"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Nathanael H Green, Daniel L Galvan, Shawn S Badal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MTHFD2 links RNA methylation to metabolic reprogramming in renal cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-019-0869-4"}], "href": "https://doi.org/10.1038/s41388-019-0869-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31289360"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31289360"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "R Nilsson, V Nicolaidou, C Koufaris "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial MTHFD isozymes display distinct expression, regulation, and association with cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2019.144032"}], "href": "https://doi.org/10.1016/j.gene.2019.144032"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31377316"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31377316"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Chantal Hoi Yin Cheung, Chia-Lang Hsu, Chao-Yin Tsuei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-019-2033-z"}], "href": "https://doi.org/10.1038/s41419-019-2033-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31624245"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31624245"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Chang Yu, Lehe Yang, Mengsi Cai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Down-regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle-related genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.14844"}], "href": "https://doi.org/10.1111/jcmm.14844"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31778025"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31778025"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Huan He, Peng-Cheng Li, Wei Jia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High Expression of Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) in Esophageal Squamous Cell Carcinoma and its Clinical Prognostic Significance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Sci Monit (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.12659/MSM.920259"}], "href": "https://doi.org/10.12659/MSM.920259"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32088725"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32088725"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Vicky Nicolaidou, Christos Papaneophytou, Costas Koufaris "}, {"type": "b", "children": [{"type": "t", "text": "Detection and characterisation of novel alternative splicing variants of the mitochondrial folate enzyme MTHFD2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11033-020-05775-y"}], "href": "https://doi.org/10.1007/s11033-020-05775-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32880830"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32880830"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Jianlin Wang, Judong Luo, Zhiqiang Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of MTHFD2 as a novel prognosis biomarker in esophageal carcinoma patients based on transcriptomic data and methylation profiling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Medicine (Baltimore) (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MD.0000000000022194"}], "href": "https://doi.org/10.1097/MD.0000000000022194"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32925794"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32925794"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Q-Q Geng, Q-F Wu, Y Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical significance of circ-MTHFD2 in diagnosis, pathological staging and prognosis of NSCLC."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Rev Med Pharmacol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.26355/eurrev_202009_23032"}], "href": "https://doi.org/10.26355/eurrev_202009_23032"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33015789"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33015789"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Kazuhiro Tanaka, Takashi Sasayama, Hiroaki Nagashima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glioma cells require one-carbon metabolism to survive glutamine starvation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Neuropathol Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s40478-020-01114-1"}], "href": "https://doi.org/10.1186/s40478-020-01114-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33468252"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33468252"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Man Shang, Huijie Yang, Ran Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-021-22173-5"}], "href": "https://doi.org/10.1038/s41467-021-22173-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33782411"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33782411"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Yangfeng Shi, Yiming Xu, Jianchang Yao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MTHFD2 promotes tumorigenesis and metastasis in lung adenocarcinoma by regulating AKT/GSK-3β/β-catenin signalling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.16715"}], "href": "https://doi.org/10.1111/jcmm.16715"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34121323"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34121323"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Qiutong Li, Fang Yang, Xiu Shi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MTHFD2 promotes ovarian cancer growth and metastasis via activation of the STAT3 signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Open Bio (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/2211-5463.13249"}], "href": "https://doi.org/10.1002/2211-5463.13249"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34231329"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34231329"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Gen Li, Jun Wu, Le Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "p53 deficiency induces MTHFD2 transcription to promote cell proliferation and restrain DNA damage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2019822118"}], "href": "https://doi.org/10.1073/pnas.2019822118"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34244426"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34244426"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Xi Liu, Shuangjie Liu, Chiyuan Piao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Non-metabolic function of MTHFD2 activates CDK2 in bladder cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.15159"}], "href": "https://doi.org/10.1111/cas.15159"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34632667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34632667"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Xiangrong Cui, Huancheng Su, Jiaolin Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Up-regulation of MTHFD2 is associated with clinicopathological characteristics and poor survival in ovarian cancer, possibly by regulating MOB1A signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Ovarian Res (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13048-022-00954-w"}], "href": "https://doi.org/10.1186/s13048-022-00954-w"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35135596"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35135596"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Nadilly Bonagas, Nina M S Gustafsson, Martin Henriksson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cancer (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s43018-022-00331-y"}], "href": "https://doi.org/10.1038/s43018-022-00331-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35228749"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35228749"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Fan Zhang, Di Wang, Jintao Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Cell Biol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jmcb/mjac020"}], "href": "https://doi.org/10.1093/jmcb/mjac020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35349697"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35349697"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Qian Chen, Peng Huang, Xin-Li Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Association of maternal "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "MTHFD1"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " and "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "MTHFD2"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " gene polymorphisms with congenital heart disease in offspring]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhongguo Dang Dai Er Ke Za Zhi (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7499/j.issn.1008-8830.2203002"}], "href": "https://doi.org/10.7499/j.issn.1008-8830.2203002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35894196"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35894196"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Yixing Gao, Lan Feng, Luping Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ATF4/MYC Regulates MTHFD2 to Promote NSCLC Progression by Mediating Redox Homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dis Markers (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2022/7527996"}], "href": "https://doi.org/10.1155/2022/7527996"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36051358"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36051358"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Zhiyuan Zhu, Karrie Mei-Yee Kiang, Ning Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2022.215903"}], "href": "https://doi.org/10.1016/j.canlet.2022.215903"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36089117"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36089117"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Abhinav Achreja, Tao Yu, Anjali Mittal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Metab (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s42255-022-00636-3"}], "href": "https://doi.org/10.1038/s42255-022-00636-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36131208"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36131208"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Meihui Huang, Jiajian Xue, Zhiming Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MTHFD2 suppresses glioblastoma progression via the inhibition of ERK1/2 phosphorylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Cell Biol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1139/bcb-2022-0291"}], "href": "https://doi.org/10.1139/bcb-2022-0291"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36493392"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36493392"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Xinxi Deng, Xiaoqiang Liu, Bing Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijmm.2022.5217"}], "href": "https://doi.org/10.3892/ijmm.2022.5217"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36601741"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36601741"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Sa Wu, Weisong Cai, Yanli Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SNHG3/hsa-miR-455-5p Axis-mediated High Expression of MTHFD2 Correlates with Tumor Immune Infiltration and Endometrial Carcinoma Progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Med Sci (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7150/ijms.81962"}], "href": "https://doi.org/10.7150/ijms.81962"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37484807"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37484807"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Jie Wang, Ze Yu, Yixiao Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of MTHFD2 Inhibits Proliferation and Enhances Chemosensitivity in Hepatocellular Carcinoma via PI3K/AKT Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Biosci (Landmark Ed) (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.31083/j.fbl2901035"}], "href": "https://doi.org/10.31083/j.fbl2901035"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38287824"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38287824"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Rafaela V N Silva, Lucas A Berzotti, Marcella G Laia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Implications of MTHFD2 expression in renal cell carcinoma aggressiveness."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0299353"}], "href": "https://doi.org/10.1371/journal.pone.0299353"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38422037"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38422037"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Hai-Yu Mo, Ruo-Bing Wang, Meng-Yao Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Redox Rep (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/13510002.2024.2345455"}], "href": "https://doi.org/10.1080/13510002.2024.2345455"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38723197"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38723197"}]}]}]}