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Background <p>The 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.</p> Methods <p>We 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.</p> Results <p>AHR 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.</p> Conclusions <p>Our 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.</p> Clinical trial number <p>Not applicable.</p>

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Investigating the interaction between aryl hydrocarbon receptor and methotrexate: implications for treatment resistance in rheumatoid arthritis patients

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • Anna Wajda,
  • Gabriela Filipowicz,
  • Yana Kaliberda,
  • Barbara Stypińska,
  • Tomasz Kmiołek,
  • Ewa Kuca-Warnawin,
  • Małgorzata Jarończyk,
  • Agata Matusiewicz,
  • Bożena Jaszczyk,
  • Małgorzata Stasiek,
  • Anna Felis-Giemza,
  • Katarzyna Bazała,
  • Adam Ejma-Multański,
  • Diana Bogucka,
  • Ewa Modzelewska,
  • Marzena Olesińska,
  • Agnieszka Paradowska-Gorycka

摘要

Background

The 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.

Methods

We 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.

Results

AHR 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.

Conclusions

Our 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.