ArticlePharmacological reports : PR2026
Investigating the interaction between aryl hydrocarbon receptor and methotrexate: implications for treatment resistance in rheumatoid arthritis patients.
Article in Pharmacological reports : PR, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundThe aryl hydrocarbon receptor (AHR) plays a key role in immune regulation and drug metabolism, potentially influencing methotrexate (MTX) treatment outcomes in patients with rheumatoid arthritis (RA). This exploratory study investigated the relationship between AHR activity and MTX responsiveness, and examined whether combination therapy with tocilizumab (TCZ), an interleukin (IL)-6 receptor inhibitor, could influence MTX resistance and treatment response.
methodsWe employed in silico docking to assess MTX binding to the AHR Per-Arnt-Sim (PAS)-B domain. Ex vivo and in vitro models using peripheral blood mononuclear cells (PBMCs) from RA patients and healthy donors were also used. Flow cytometry was used to analyze AHR expression across immune cell subtypes. Additionally, HepG2 cells served as a pharmacological model to study the interaction of MTX and TCZ with AHR and the expression of drug transporter genes.
resultsAHR expression was significantly higher in monocytes from good responders to MTX than in those from poor responders and MTX-intolerant patients, suggesting that monocytes were the PBMC subset most strongly associated with AHR-related patterns of MTX response. In silico analysis supported the binding of MTX to the PAS-B domain of AHR. The in vitro model confirmed that monocytes were the most responsive subset in the context of AHR-related changes. Treatment with TCZ tended to reduce the proportion of AHR-positive monocytes, whereas co-treatment with MTX shifted AHR toward a pattern comparable to that in good responders or under control conditions.
conclusionsOur findings underscore the complexity of MTX pharmacodynamics and highlight AHR as a potential biomarker for predicting treatment response in RA patients. The combination of MTX and TCZ modulated AHR activity and could inform personalized therapeutic strategies, especially in patients exhibiting MTX resistance or intolerance. While preliminary, this multi-layered investigation-combining patient samples, 3D cultures, and molecular docking-supports further research into AHR-modulating therapies in RA. CLINICAL TRIAL NUMBER: Not applicable.
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