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Early-stage availability may protect against malignant transformation through improved DNA repair and epigenetic stability, whereas later cancer cells can hijack these nutrients to support proliferation and tumor progression. The paper reframes methyl donors as context-dependent modifiers shaped by timing, metabolic status, and tissue biology, supporting precision nutrition strategies for prevention or targeted 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is the relationship between methyl donors and cancer considered paradoxical?","Question",{"text":63,"@type":64},"Their effects vary across the cancer continuum, and many misunderstandings come from relying on epidemiological endpoints that reflect late-stage outcomes rather than phase-specific biology.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How might methyl donors protect during early cancer development?",{"text":68,"@type":64},"Adequate methyl-donor availability may support DNA repair, limit mutation accumulation, and maintain normal epigenetic programming in the earliest phases.",{"name":70,"@type":61,"acceptedAnswer":71},"How can the same methyl donors contribute to tumor progression later on?",{"text":72,"@type":64},"Once neoplastic cells are established, excess methyl donors may be used as substrates to fuel rapid proliferation, maintain oncogenic methylation programs, and enhance progression in established malignancies and high-risk 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Donors in Cancer Development from Prevention to Progression  \nDa Pan *, Shaokang Wang  and Guiju Sun *  \nAcademic Editor: Peter J. K. Kuppen  \nReceived: 3 December 2025  \nRevised: 25 December 2025  \nAccepted: 26 December 2025  \nPublished: 28 December 2025  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \nKey Laboratory of Environmental Medicine and Engineering, Ministry of Education, Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing 210009, China; [shaokangwang@seu.edu.cn](shaokangwang@seu.edu.cn)  \n* [Correspondence: pan_da@seu.edu.cn](Correspondence: pan_da@seu.edu.cn) (D.P.); [gjsun@seu.edu.cn](gjsun@seu.edu.cn) (G.S.); Tel.: +86-025-83272567 (G.S.)  \nAbstract  \nMethyl-donor nutrients, including folate, vitamin B12, vitamin B6, choline, betaine, and methionine, play indispensable roles in one-carbon metabolism and govern key processes such as DNA methylation, nucleotide synthesis, and genomic maintenance. 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.  \nKeywords: one-carbon metabolism; methyl-donor nutrients; cancer prevention; dual-role hypothesis; epigenetic regulation; cancer progression; precision nutrition  \n1. Introduction  \nMethyl donors—such as folate, vitamin B12, vitamin B6, choline, betaine, and methionine—are essential nutrients that fuel one-carbon metabolism and drive methylation reactions across the genome [1] . These reactions play a central role in maintaining epigenetic homeostasis, genomic stability, and cellular integrity [2,3] . Through the transfer of methyl groups, methyl donors regulate DNA methylation, RNA processing, and histone modification, thereby influencing gene expression patterns that determine cell fate, differentiation, and response to environmental stimuli [4] .  \nAberrant methylation has long been recognized as a hallmark of cancer. Global hypomethylation can activate oncogenes and destabilize chromosomal architecture, whereas regional hypermethylation may silence tumor suppressor genes [5] . Given their role in modulating methylation capacity, nutritional methyl donors have emerged as critical dietary factors that can either prevent or promote tumorigenesis, depending on context and  \ntiming [6] . Accumulating evidence suggests a potential biphasic role of methyl donors during the cancer continuum. For instance, researchers proposed a hypothesis based on conflicting research findings [7], suggesting that in the early stages, adequate methyl donor availability supports DNA repair, limits mutation accumulation, and maintains normal epigenetic programming","cbCaidQ4O1DavYoi","https://ap.wps.com/l/cbCaidQ4O1DavYoi","pdf",758185,"English","# Abstract\n# 1. Introduction\n# 2. Overview of Methyl Donors and One-Carbon Metabolism\n## 2.1. Key Nutrients and Pathways","[{\"question\":\"Why is the relationship between methyl donors and cancer considered paradoxical?\",\"answer\":\"Their effects vary across the cancer continuum, and many misunderstandings come from relying on epidemiological endpoints that reflect late-stage outcomes rather than phase-specific biology.\"},{\"question\":\"How might methyl donors protect during early cancer development?\",\"answer\":\"Adequate methyl-donor availability may support DNA repair, limit mutation accumulation, and maintain normal epigenetic programming in the earliest phases.\"},{\"question\":\"How can the same methyl donors contribute to tumor progression later on?\",\"answer\":\"Once neoplastic cells are established, excess methyl donors may be used as substrates to fuel rapid proliferation, maintain oncogenic methylation programs, and enhance progression in established malignancies and high-risk populations.\"}]","The Double-Edged Nature of Methyl Donors in Cancer Development from Prevention to Progression | PDF",1790763210,48]