{
  "abstract": "Folate is co-administered with fluoropyrimidines in colorectal cancer to potentiate thymidylate synthase inhibition, yet its therapeutic effects are paradoxically inconsistent across disease and treatment settings. Here we show that one-carbon metabolism remodels epithelial identity before treatment and thereby alters fluoropyrimidine response. Folate restoration shifted colorectal cancer cells along a polarized epithelial axis from a stem-like toward a differentiated state, whereas folate deprivation favored the opposite configuration. These pretreatment states differed markedly in 5-fluorouracil sensitivity. Folate restoration increased sensitivity across colorectal cancer cell lines and patient-derived organoids, whereas folate deprivation or methotrexate increased therapy-induced senescence. State-dependent sensitivity was not explained by proliferation alone, as stem-like cells were least responsive under the same conditions in which their S-phase occupancy was highest. Mechanistically, folate restoration increased methylation potential, supported EZH2-dependent H3K27me3 remodeling, reorganized chromatin accessibility and transcription-factor engagement, and reduced canonical WNT activity. In human colorectal tissue, stem-like program activity was higher and differentiation program activity lower in carcinoma than in normal mucosa, with adenomas intermediate, a pattern opposite to folate-induced remodeling. Folate is therefore not merely a cofactor for thymidylate synthase inhibition but an instructive metabolic regulator of the epithelial state that stratifies fluoropyrimidine response.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "L. Vizkeleti"
    },
    {
      "name": "C. Kiss"
    },
    {
      "name": "V. Tisza"
    },
    {
      "name": "A. Zichy"
    },
    {
      "name": "A. Markovics"
    },
    {
      "name": "A. Kalmar"
    },
    {
      "name": "P. Szabo"
    },
    {
      "name": "I. Csabai"
    },
    {
      "name": "L. Pongor"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Spisak"
    },
    {
      "name": "B. Molnar"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8c9s6n4czn2a2.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.30.755690",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755690v1.full",
  "id": "8c9s6n4czn2a2",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755690v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "molecular biology"
    ],
    [
      "openalex",
      "1312|Epigenetics and DNA Methylation"
    ]
  ],
  "openalex": "W7216211798",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755690v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/8c9s6n4czn2a2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:46Z",
      "native_id": "10.64898/2026.09.30.755690",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.30.755690v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:molecular biology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "One-carbon metabolism controls colorectal cancer cell state and chemosensitivity through chromatin remodeling",
  "title_text": "One-carbon metabolism controls colorectal cancer cell state and chemosensitivity through chromatin remodeling",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:46Z",
  "url": "https://research.draconitic.com/paper/8c9s6n4czn2a2",
  "venue": "bioRxiv",
  "versions": []
}