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How does methotrexate work?

Adel M Alqarni1, Martin P Zeidler1

  • 1Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, U.K.

Biochemical Society Transactions
|April 3, 2020
PubMed
Summary
This summary is machine-generated.

Methotrexate (MTX), an essential medicine, effectively treats autoimmune diseases. New evidence suggests MTX primarily works by inhibiting the JAK/STAT pathway, not the folate pathway, opening doors for new therapeutic uses.

Keywords:
drug effectspharmacologyrepurposing

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Area of Science:

  • Immunology
  • Pharmacology
  • Rheumatology

Background:

  • Methotrexate (MTX) is a cornerstone therapy for autoimmune and inflammatory diseases like rheumatoid arthritis (RA).
  • Low-dose MTX is widely used weekly for effective inflammatory control in millions globally.
  • The precise anti-inflammatory mechanism of low-dose MTX remains incompletely understood.

Purpose of the Study:

  • To investigate the mechanism of action of low-dose methotrexate in treating inflammatory diseases.
  • To evaluate the role of the JAK/STAT pathway versus the folate pathway in MTX's therapeutic effects.
  • To explore potential new applications for MTX based on its elucidated mechanism.

Main Methods:

  • Review and synthesis of existing evidence on MTX's molecular targets.
  • Analysis of studies investigating MTX's effects on inflammatory and immune pathways.
  • Comparison of proposed mechanisms with clinical observations of MTX efficacy and side effects.

Main Results:

  • Evidence suggests MTX inhibits the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway.
  • The traditional view of MTX acting primarily via the folate pathway for anti-inflammatory effects is questioned.
  • JAK/STAT pathway inhibition aligns with MTX's role in immune and inflammatory regulation.

Conclusions:

  • The anti-inflammatory activity of disease-modifying anti-rheumatic drug (DMARD) methotrexate is likely mediated by JAK/STAT pathway inhibition.
  • Folate pathway interactions may be more closely linked to MTX's side effects.
  • Understanding MTX's mechanism could enable repurposing for other JAK/STAT-mediated diseases.