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Repurposing the antihistamine cyproheptadine for osteoarthritis: nothing to sneeze at

Richard F Loeser1,2, Philip R Coryell1

  • 1Thurston Arthritis Research Center and.

The Journal of Clinical Investigation
|November 3, 2025
PubMed

Insights

The antihistamine cyproheptadine activates Forkhead box O (FOXO) transcription factors, potentially treating osteoarthritis. This drug reduced joint damage and pain in a mouse model, showing promise for osteoarthritis therapeutics.

Area of Science:

  • Biomedical research
  • Pharmacology
  • Molecular biology

Background:

  • Osteoarthritis (OA) is a widespread, painful joint condition lacking disease-modifying treatments.
  • Reduced activity of Forkhead box O (FOXO) transcription factors in chondrocytes is implicated in OA development.

Purpose of the Study:

  • To identify compounds that activate FOXO transcription factors.
  • To evaluate the therapeutic potential of FOXO activators for osteoarthritis.

Main Methods:

  • Screening of compounds for FOXO activation.
  • Investigating the mechanism of action, including histamine H1 receptor inhibition.
  • Assessing the effects of cyproheptadine in a mouse model of OA.

Main Results:

  • Cyproheptadine was identified as a FOXO activator via histamine H1 receptor inhibition.
  • Cyproheptadine modulated key pathways relevant to osteoarthritis.
  • Treatment with cyproheptadine decreased joint damage and pain behaviors in an OA mouse model.

Conclusions:

  • Cyproheptadine shows potential as a disease-modifying osteoarthritis drug.
  • Targeting FOXO activation represents a promising therapeutic strategy for OA.
  • Further development of cyproheptadine could lead to novel OA treatments.

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