Component

Methotrexate

Antifolate; experimental exposures are not supplementation advice.

7 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What it acts on

  1. Methotrexate inhibited the RFC-mediated component of thiamine-monophosphate influx in mouse L1210 cells.

    Methotrexate → Thiamine monophosphate source_derived_draftungraded
    Experimental context and source evidence
    cross_nutrient
    B1-antifolate: competition at RFC under the tested drug exposure.
    experimental_model
    Mouse L1210/R16 leukemia transport experiments
    exposure
    50 nM TMP with 100 micromolar methotrexate
    limitations
    Pharmacological cell experiment, not a clinical thiamine-deficiency outcome.
    nutrient_topic
    Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
    organism
    Mus musculus
    plain_language
    An antifolate competed with phosphorylated B1 entry.
    primary_references
    [zhao2002] Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells (2002). https://pubmed.ncbi.nlm.nih.gov/11997266/ DOI: 10.1152/ajpcell.00547.2001
    tissue_or_cell_type
    L1210 leukemia cells

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 193–204

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse L1210/R16 leukemia transport experiments · source_derived_draft · unverified_draft

    ### folate-mtx-tmp-transport-competition Methotrexate inhibited the RFC-mediated component of thiamine-monophosphate influx in mouse L1210 cells. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: An antifolate competed with phosphorylated B1 entry. organism: Mus musculus tissue_or_cell_type: L1210 leukemia cells experimental_model: Mouse L1210/R16 leukemia transport experiments limitations: Pharmacological cell experiment, not a clinical thiamine-deficiency outcome. exposure: 50 nM TMP with 100 micromolar methotrexate cross_nutrient: B1-antifolate: competition at RFC under the tested drug exposure. [zhao2002] Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells (2002). https://pubmed.ncbi.nlm.nih.gov/11997266/ DOI: 10.1152/ajpcell.00547.2001
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. CRISPR depletion of AMDHD1 reduced methotrexate sensitivity in the tested human cancer cells.

    Human imidazolonepropionase / AMDHD1 → Methotrexate sensitivity in human hematopoietic cancer cells source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary full text
    experimental_model
    Human hematopoietic cancer-cell CRISPR experiments.
    limitations
    Enzyme depletion is different from lowering dietary histidine. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
    nutrient_topic
    L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
    plain_language
    An upstream histidine-breakdown step also changed drug sensitivity.
    primary_references
    Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 170–176

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human hematopoietic cancer-cell CRISPR experiments. · source_derived_draft · unverified_draft

    ## histidine-amdhd-loss-mtx An upstream histidine-breakdown step also changed drug sensitivity. CRISPR depletion of AMDHD1 reduced methotrexate sensitivity in the tested human cancer cells. Model: Human hematopoietic cancer-cell CRISPR experiments. Limitations: Enzyme depletion is different from lowering dietary histidine. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
    Complete structured claim and evidence

  2. CRISPR depletion of FTCD reduced methotrexate sensitivity in HEL, Ramos and LAMA84 cells; an sgRNA-resistant murine Ftcd construct restored sensitivity in the rescue experiment.

    Human formimidoyltransferase cyclodeaminase / FTCD → Methotrexate sensitivity in human hematopoietic cancer cells source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary full text
    experimental_model
    Human cancer lines, CRISPR/RNAi and mouse-cDNA rescue.
    limitations
    Drug-exposed culture and cross-species rescue; not evidence that histidine is universally harmful or beneficial. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
    nutrient_topic
    L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
    plain_language
    Removing this histidine-processing step made the tested cancer cells less sensitive to the drug.
    primary_references
    Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 146–152

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer lines, CRISPR/RNAi and mouse-cDNA rescue. · source_derived_draft · unverified_draft

    ## histidine-ftcd-loss-mtx Removing this histidine-processing step made the tested cancer cells less sensitive to the drug. CRISPR depletion of FTCD reduced methotrexate sensitivity in HEL, Ramos and LAMA84 cells; an sgRNA-resistant murine Ftcd construct restored sensitivity in the rescue experiment. Model: Human cancer lines, CRISPR/RNAi and mouse-cDNA rescue. Limitations: Drug-exposed culture and cross-species rescue; not evidence that histidine is universally harmful or beneficial. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
    Complete structured claim and evidence

  3. Under methotrexate, FTCD depletion preserved THF and increased serine-derived labeling of IMP and TTP relative to controls.

    Human formimidoyltransferase cyclodeaminase / FTCD → Tetrahydrofolate source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary full text
    experimental_model
    Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing.
    limitations
    Measured under methotrexate; do not generalize to normal folate demand or all tissues. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
    nutrient_topic
    L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
    plain_language
    Blocking histidine breakdown spared folate for nucleotide production in this drug-stressed setting.
    primary_references
    Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 154–160

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing. · source_derived_draft · unverified_draft

    ## histidine-ftcd-thf-sparing Blocking histidine breakdown spared folate for nucleotide production in this drug-stressed setting. Under methotrexate, FTCD depletion preserved THF and increased serine-derived labeling of IMP and TTP relative to controls. Model: Human cancer cells with FTCD depletion, metabolomics and U-13C-serine tracing. Limitations: Measured under methotrexate; do not generalize to normal folate demand or all tissues. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
    Complete structured claim and evidence

  4. CRISPR depletion of HAL reduced methotrexate sensitivity in the tested human cancer cells.

    Human histidine ammonia-lyase / HAL → Methotrexate sensitivity in human hematopoietic cancer cells source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    machinery_impairment Imported condition classification; unverified.
    evidence_access
    Primary full text
    experimental_model
    Human hematopoietic cancer-cell CRISPR experiments.
    limitations
    Enzyme depletion is different from lowering dietary histidine. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
    nutrient_topic
    L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
    plain_language
    An upstream histidine-breakdown step also changed drug sensitivity.
    primary_references
    Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
    trigger_kind
    machinery_impairment Imported condition classification; unverified.

    L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 162–168

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human hematopoietic cancer-cell CRISPR experiments. · source_derived_draft · unverified_draft

    ## histidine-hal-loss-mtx An upstream histidine-breakdown step also changed drug sensitivity. CRISPR depletion of HAL reduced methotrexate sensitivity in the tested human cancer cells. Model: Human hematopoietic cancer-cell CRISPR experiments. Limitations: Enzyme depletion is different from lowering dietary histidine. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
    Complete structured claim and evidence

  5. Combined histidine and methotrexate reduced HEL/SEM xenograft size more than either single treatment in the reported main mouse experiment.

    L-Histidine → Methotrexate response of human leukemia xenografts in mice source_derived_draftungraded
    Experimental context and source evidence
    evidence_access
    Primary full text
    experimental_model
    NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg.
    limitations
    Main methods specify injections despite dietary terminology in the abstract. No oral human combination trial or treatment recommendation; longer mouse experiments do not establish human safety. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2
    nutrient_topic
    L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine
    plain_language
    Changing substrate supply strengthened a drug effect in this animal model.
    primary_references
    Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7

    L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 178–184

    AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg. · source_derived_draft · unverified_draft

    ## histidine-histidine-mtx-xenograft Changing substrate supply strengthened a drug effect in this animal model. Combined histidine and methotrexate reduced HEL/SEM xenograft size more than either single treatment in the reported main mouse experiment. Model: NOD-SCID mice with human leukemia xenografts; daily injections for five days, histidine 400 microliters at 46 mg/mL and methotrexate 50 mg/kg. Limitations: Main methods specify injections despite dietary terminology in the abstract. No oral human combination trial or treatment recommendation; longer mouse experiments do not establish human safety. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2 Evidence access: Primary full text Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7
    Complete structured claim and evidence

  6. Human SLC19A1 bound thiamine diphosphate in the same pocket as 5-MTHF; thiamine diphosphate inhibited methotrexate uptake with IC50 about 19 micromolar.

    Thiamine diphosphate → Human reduced folate carrier / SLC19A1 source_derived_draftungraded
    Experimental context and source evidence
    cross_nutrient
    B1-folate: phosphorylated thiamine and folates share RFC recognition; exclusive physiological counter-substrate status remains unproven.
    experimental_model
    Human SLC19A1 structures and HEK293F uptake assays
    exposure
    Binding assays and extracellular competition
    limitations
    Supports shared recognition; does not prove dietary B1 deficiency blocks folate delivery.
    nutrient_topic
    Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
    organism
    Homo sapiens
    plain_language
    A vitamin B1 cofactor can occupy the folate carrier.
    primary_references
    [dang2022] Molecular mechanism of substrate recognition by folate transporter SLC19A1 (2022). https://pubmed.ncbi.nlm.nih.gov/36575193/ DOI: 10.1038/s41421-022-00508-w
    tissue_or_cell_type
    Purified transporter and HEK293F cells

    Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 167–178

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human SLC19A1 structures and HEK293F uptake assays · source_derived_draft · unverified_draft

    ### folate-rfc-thdp-shared-pocket Human SLC19A1 bound thiamine diphosphate in the same pocket as 5-MTHF; thiamine diphosphate inhibited methotrexate uptake with IC50 about 19 micromolar. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A vitamin B1 cofactor can occupy the folate carrier. organism: Homo sapiens tissue_or_cell_type: Purified transporter and HEK293F cells experimental_model: Human SLC19A1 structures and HEK293F uptake assays limitations: Supports shared recognition; does not prove dietary B1 deficiency blocks folate delivery. exposure: Binding assays and extracellular competition cross_nutrient: B1-folate: phosphorylated thiamine and folates share RFC recognition; exclusive physiological counter-substrate status remains unproven. [dang2022] Molecular mechanism of substrate recognition by folate transporter SLC19A1 (2022). https://pubmed.ncbi.nlm.nih.gov/36575193/ DOI: 10.1038/s41421-022-00508-w
    Complete structured claim and evidence

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

    This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

    Evidence, AI assistance and curation standards