{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:42:14Z","timestamp":1785426134684,"version":"3.56.0"},"reference-count":57,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373571"],"award-info":[{"award-number":["82373571"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82373571"],"award-info":[{"award-number":["82373571"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, yet the association between folic acid (FA) intake and CRC risk remains controversial. This study investigated the effects of varying dietary FA levels on colorectal carcinogenesis and the underlying mechanisms. Methods: BALB\/c mice were fed diets containing FA at &lt;0.1, 2.0, 6.0, 8.0, or 20.0 mg\/kg for 14 weeks. After 4 weeks, colorectal tumorigenesis was induced using the azoxymethane\/dextran sulfate sodium (AOM\/DSS) protocol. Tumor multiplicity, maximum tumor diameter, tumor volume, colorectal length, histopathology, and cell proliferation were assessed. Mechanistic assessments included uracil misincorporation, thymidylate synthase (TS), telomere attrition, genome-wide DNA methylation, RAP1 signaling, immune-related markers, and inflammatory cytokines in colorectal tissues. Results: Both FA deficiency (&lt;0.1 mg\/kg) and excess (8.0\/20.0 mg\/kg) increased colorectal tumor burden, with increased tumor number, larger maximum diameter, greater tumor volume, shortened colorectal length, and enhanced cell proliferation, whereas the 6.0 mg\/kg diet group showed the lowest tumor burden. FA deficiency reduced TS expression, elevated deoxyuridine monophosphate (dUMP) levels, decreased deoxythymidine monophosphate (dTMP) levels, increased uracil misincorporation, and exacerbated telomere attrition, as evidenced by shortened telomeres and increased damage. In contrast, excessive FA intake induced Rap1 GTPase-activating protein (RAP1GAP) hypermethylation, reduced Rap1GAP expression, enhanced RAP1 activity, and upregulated programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) expression. Conclusions: Dietary FA can exhibit a U-shaped association with colorectal carcinogenesis, with protective effects observed within an optimal range. FA deficiency and excess may drive tumor development through distinct molecular pathways involving uracil misincorporation-induced telomere attrition and DNA methylation-mediated immunosuppression, respectively.<\/jats:p>","DOI":"10.3390\/nu18081187","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T07:55:12Z","timestamp":1775807712000},"page":"1187","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deficiency and Excess of Folic Acid Intake Promote Colorectal Carcinogenesis in AOM\/DSS-Treated Mice: Roles in Uracil Misincorporation and DNA Methylation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0109-2256","authenticated-orcid":false,"given":"Qinghan","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2286-1557","authenticated-orcid":false,"given":"Yunfei","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0117-653X","authenticated-orcid":false,"given":"Zhenshu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China"},{"name":"Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, Tianjin Medical University, Tianjin 300070, China"},{"name":"Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China"},{"name":"The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin 300070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6108-644X","authenticated-orcid":false,"given":"Qi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7958-2562","authenticated-orcid":false,"given":"Tongtong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0813-4786","authenticated-orcid":false,"given":"Xin","family":"He","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9268-538X","authenticated-orcid":false,"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China"},{"name":"Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, Tianjin Medical University, Tianjin 300070, China"},{"name":"Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China"},{"name":"The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin 300070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2559-498X","authenticated-orcid":false,"given":"Yongjie","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology & Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9742-4920","authenticated-orcid":false,"given":"Fei","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Epidemiology & Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0203-8451","authenticated-orcid":false,"given":"Jing","family":"Yan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, Tianjin 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Nutr. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Thanikachalam, K., and Khan, G. (2019). Colorectal Cancer and Nutrition. Nutrients, 11.","DOI":"10.3390\/nu11010164"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.ajcnut.2024.07.012","article-title":"Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing","volume":"120","author":"Aglago","year":"2024","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3945\/an.112.003392","article-title":"Folate","volume":"4","author":"Chan","year":"2013","journal-title":"Adv. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1002\/ijc.20648","article-title":"Folate intake and colorectal cancer risk: A meta-analytical approach","volume":"113","author":"Sanjoaquin","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1001\/jama.297.21.2351","article-title":"Folic acid for the prevention of colorectal adenomas: A randomized clinical trial","volume":"297","author":"Cole","year":"2007","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3945\/ajcn.2009.28527","article-title":"Uracil misincorporation into DNA and folic acid supplementation","volume":"91","author":"Hazra","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1016\/j.clnu.2017.10.010","article-title":"Folic acid intake and folate status and colorectal cancer risk: A systematic review and meta-analysis","volume":"37","author":"Moazzen","year":"2018","journal-title":"Clin. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.mrgentox.2018.08.012","article-title":"Folate, genomic stability and colon cancer: The use of single cell gel electrophoresis in assessing the impact of folate in vitro, in vivo and in human biomonitoring","volume":"843","author":"Catala","year":"2019","journal-title":"Mutat. Res. Genet. Toxicol. Environ. Mutagen."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1182\/blood.2021014299","article-title":"Telomeres, aging, and cancer: The big picture","volume":"139","author":"Lansdorp","year":"2022","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"108796","DOI":"10.1016\/j.jnutbio.2021.108796","article-title":"Folic acid alleviates age-related cognitive decline and inhibits apoptosis of neurocytes in senescence-accelerated mouse prone 8: Deoxythymidine triphosphate biosynthesis as a potential mechanism","volume":"97","author":"Zhou","year":"2021","journal-title":"J. Nutr. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e10292","DOI":"10.15252\/emmm.201910292","article-title":"Multiple cancer pathways regulate telomere protection","volume":"11","author":"Bejarano","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.canlet.2014.02.024","article-title":"How folate metabolism affects colorectal cancer development and treatment; a story of heterogeneity and pleiotropy","volume":"356","author":"Jennings","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1089\/ars.2012.4554","article-title":"Folate and DNA methylation","volume":"17","author":"Ly","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13073-024-01344-1","article-title":"Colorectal cancer microbiome programs DNA methylation of host cells by affecting methyl donor metabolism","volume":"16","author":"Liu","year":"2024","journal-title":"Genome Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1079\/PNS2003265","article-title":"Folate, DNA methylation and colo-rectal cancer","volume":"62","author":"Pufulete","year":"2003","journal-title":"Proc. Nutr. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13578-026-01534-x","article-title":"DNA methylation-mediated silencing of MEOX1 promotes glycolysis and immune evasion in colorectal cancer cells through inhibition of GLP2R transcription","volume":"16","author":"Liang","year":"2026","journal-title":"Cell Biosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"17602","DOI":"10.1038\/s41598-019-54070-9","article-title":"Effect of imbalance in folate and vitamin B12 in maternal\/parental diet on global methylation and regulatory miRNAs","volume":"9","author":"Mahajan","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.canlet.2013.07.032","article-title":"Chronic ulcerative colitis and colorectal cancer","volume":"345","author":"Rogler","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1017\/S0007114520000422","article-title":"One-carbon metabolites, B vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients: Results from the ColoCare Study","volume":"123","author":"Kiblawi","year":"2020","journal-title":"Br. J. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1038\/s42255-025-01347-1","article-title":"Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment","volume":"7","author":"Xu","year":"2025","journal-title":"Nat. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1093\/jn\/123.11.1939","article-title":"AIN-93 purified diets for laboratory rodents: Final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet","volume":"123","author":"Reeves","year":"1993","journal-title":"J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Chang, W.L., Ghosh, J., Cooper, H.S., Vanderveer, L., Schultz, B., Zhou, Y., Harvey, K.N., Kaunga, E., Devarajan, K., and Li, Y. (2023). Folic Acid Supplementation Promotes Hypomethylation in Both the Inflamed Colonic Mucosa and Colitis-Associated Dysplasia. Cancers, 15.","DOI":"10.3390\/cancers15112949"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Fardous, A.M., Beydoun, S., James, A.A., Ma, H., Cabelof, D.C., Unnikrishnan, A., and Heydari, A.R. (2021). The Timing and Duration of Folate Restriction Differentially Impacts Colon Carcinogenesis. Nutrients, 14.","DOI":"10.3390\/nu14010016"},{"key":"ref_26","first-page":"5434","article-title":"Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse","volume":"60","author":"Song","year":"2000","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5350","DOI":"10.1002\/ptr.8303","article-title":"N-palmitoyl-d-glucosamine limits mucosal damage and VEGF-mediated angiogenesis by PPAR\u03b1-dependent suppression of pAkt\/mTOR\/HIF1\u03b1 pathway and increase in PEA levels in AOM\/DSS colorectal carcinoma in mice","volume":"38","author":"Palenca","year":"2024","journal-title":"Phytother. Res. PTR"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1186\/s12935-024-03428-9","article-title":"Therapeutic potential of Pien Tze Huang in colitis-associated colorectal cancer: Mechanistic insights from a mouse model","volume":"24","author":"Liu","year":"2024","journal-title":"Cancer Cell Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1007\/s12035-021-02623-3","article-title":"Alleviating Oxidative Damage-Induced Telomere Attrition: A Potential Mechanism for Inhibition by Folic Acid of Apoptosis in Neural Stem Cells","volume":"59","author":"Li","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103853","DOI":"10.1016\/j.drudis.2023.103853","article-title":"Medicinal chemistry aspects of uracil containing dUTPase inhibitors targeting colorectal cancer","volume":"29","author":"Backer","year":"2024","journal-title":"Drug Discov. Today"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1158\/1940-6207.CAPR-13-0264","article-title":"Folate deficiency induces dysfunctional long and short telomeres; both states are associated with hypomethylation and DNA damage in human WIL2-NS cells","volume":"7","author":"Bull","year":"2014","journal-title":"Cancer Prev. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1002\/cac2.12149","article-title":"Mex3a promotes oncogenesis through the RAP1\/MAPK signaling pathway in colorectal cancer and is inhibited by hsa-miR-6887-3p","volume":"41","author":"Li","year":"2021","journal-title":"Cancer Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"118260","DOI":"10.1016\/j.jep.2024.118260","article-title":"Early administration of Wumei Wan inhibit myeloid-derived suppressor cells via PI3K\/Akt pathway and amino acids metabolism to prevent colitis-associated colorectal cancer","volume":"333","author":"Lu","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13045-022-01292-6","article-title":"Hypoxia-inducible factors: Master regulators of hypoxic tumor immune escape","volume":"15","author":"Wu","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1053\/j.gastro.2019.08.059","article-title":"Pathways of Colorectal Carcinogenesis","volume":"158","author":"Nguyen","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1007\/s00394-025-03720-y","article-title":"Folate intake, tissue levels, and colorectal cancer deaths in a national cohort established before folic acid fortification","volume":"64","author":"Bhattachary","year":"2025","journal-title":"Eur. J. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.3945\/ajcn.110.002659","article-title":"Pre- and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the United States","volume":"94","author":"Gibson","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_38","first-page":"116","article-title":"Folic acid supplementary reduce the incidence of adenocarcinoma in a mouse model of colorectal cancer: Microarray gene expression profile","volume":"30","author":"Lin","year":"2011","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/nature25460","article-title":"Mitochondrial translation requires folate-dependent tRNA methylation","volume":"554","author":"Morscher","year":"2018","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1158\/1055-9965.511.13.4","article-title":"Folate and DNA methylation: A mechanistic link between folate deficiency and colorectal cancer?","volume":"13","author":"Kim","year":"2004","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"127629","DOI":"10.1016\/j.foodchem.2020.127629","article-title":"Efficient fortification of folic acid in rice through ultrasonic treatment and absorption","volume":"335","author":"Tiozon","year":"2021","journal-title":"Food Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1093\/ajcn\/nqab035","article-title":"Association of folate intake and colorectal cancer risk in the postfortification era in US women","volume":"114","author":"Wang","year":"2021","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1002\/ijc.70109","article-title":"Folic acid fortification and late-onset colorectal cancer risk: A systematic assessment of the worldwide evidence","volume":"158","author":"Li","year":"2025","journal-title":"Int. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3731s","DOI":"10.1093\/jn\/133.11.3731S","article-title":"Role of folate in colon cancer development and progression","volume":"133","author":"Kim","year":"2003","journal-title":"J. Nutr."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Fardous, A.M., and Heydari, A.R. (2023). Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review. Nutrients, 15.","DOI":"10.3390\/nu15214699"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s10545-010-9128-0","article-title":"Folate and cancer: How DNA damage, repair and methylation impact on colon carcinogenesis","volume":"34","author":"Duthie","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_47","first-page":"7661","article-title":"The downregulation of Rap1 GTPase-activating protein is associated with a poor prognosis in colorectal cancer and may impact on tumor progression","volume":"15","author":"Gao","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"eaam8298","DOI":"10.1126\/scisignal.aam8298","article-title":"The adaptor molecule RIAM integrates signaling events critical for integrin-mediated control of immune function and cancer progression","volume":"10","author":"Patsoukis","year":"2017","journal-title":"Sci. Signal."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6022","DOI":"10.1158\/0008-5472.CAN-14-0657","article-title":"Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer outcomes","volume":"74","author":"Kanterman","year":"2014","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Schepelmann, M., Kupper, N., Gushchina, V., Mesteri, I., Manhardt, T., Moritsch, S., M\u00fcller, C., Piatek, K., Salzmann, M., and Vlasaty, A. (2022). AOM\/DSS Induced Colitis-Associated Colorectal Cancer in 14-Month-Old Female Balb\/C and C57\/Bl6 Mice-A Pilot Study. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095278"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"eabf2489","DOI":"10.1126\/sciimmunol.abf2489","article-title":"Mitochondrial C5aR1 activity in macrophages controls IL-1\u03b2 production underlying sterile inflammation","volume":"6","author":"Niyonzima","year":"2021","journal-title":"Sci. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"116087","DOI":"10.1016\/j.taap.2022.116087","article-title":"Folic acid ameliorates N-methyl-N\u2019-nitro-N-nitrosoguanidine-induced esophageal inflammation via modulation of the NF-\u03baB pathway","volume":"447","author":"Cheng","year":"2022","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/s41577-021-00534-x","article-title":"The inflammatory pathogenesis of colorectal cancer","volume":"21","author":"Schmitt","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e004219","DOI":"10.1136\/jitc-2021-004219","article-title":"Tumor-associated macrophage-specific CD155 contributes to M2-phenotype transition, immunosuppression, and tumor progression in colorectal cancer","volume":"10","author":"Zhu","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/sj.bjc.6604823","article-title":"Folate and colorectal cancer prevention","volume":"100","author":"Hubner","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1017\/S0029665112000717","article-title":"Folate, colorectal cancer and the involvement of DNA methylation","volume":"71","author":"Williams","year":"2012","journal-title":"Proc. Nutr. Soc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.mrrev.2012.05.001","article-title":"The influence of folate and methionine on intestinal tumour development in the Apc(Min\/+) mouse model","volume":"751","author":"Teh","year":"2012","journal-title":"Mutat. Res. Rev. Mutat. Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/8\/1187\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T08:16:01Z","timestamp":1775808961000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/8\/1187"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,9]]},"references-count":57,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["nu18081187"],"URL":"https:\/\/doi.org\/10.3390\/nu18081187","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,9]]}}}