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Yet despite decades of research, their relationship with cancer remains paradoxical and frequently misunderstood. Much of the confusion arises from an overreliance on epidemiological studies that use cancer incidence as a late-stage endpoint, thereby obscuring how the biological actions of methyl donors differ fundamentally across the continuum from precancerous lesions to established tumors. By synthesizing evidence from mechanistic studies, precancerous lesion research, and early-stage carcinogenic models, this review suggests that adequate methyl-donor availability may be protective during the earliest phases of cancer development. However, these same nutrients may later become substrates hijacked by neoplastic cells to fuel rapid proliferation, maintain oncogenic methylation programs, and enhance tumor progression in established malignancies and high-risk populations. Therefore, this review proposes a reframing that methyl donors may not be evaluated merely as protective or harmful, but rather as context-dependent modifiers whose influence is shaped by timing, metabolic status, and the underlying biology of the target tissue. Such a shift is promising for advancing precision nutrition and the prevention or targeted suppression of cancer.<\/jats:p>","DOI":"10.3390\/ijms27010323","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T05:28:19Z","timestamp":1766986099000},"page":"323","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Double-Edged Nature of Methyl Donors in Cancer Development from Prevention to Progression"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8430-9467","authenticated-orcid":false,"given":"Da","family":"Pan","sequence":"first","affiliation":[{"name":"Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7503-7655","authenticated-orcid":false,"given":"Shaokang","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5969-2185","authenticated-orcid":false,"given":"Guiju","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2333s","DOI":"10.1093\/jn\/132.8.2333S","article-title":"Diet, methyl donors and DNA methylation: Interactions between dietary folate, methionine and choline","volume":"132","author":"Niculescu","year":"2002","journal-title":"J. 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