Identifying Targets and Drugs for Rheumatoid Arthritis Stratified Therapy Using Mendelian Randomization and a Pretraining Model

Yan, Yuqing; Wu, You; Sun, Yixuan; Wu, Tian; Zhu, Haotian; Xue, Feiyang; Yu, Zhanhui; Liu, Shichao; Niu, Xiaohui

doi:10.3390/ijms26125686

Open AccessArticle

Identifying Targets and Drugs for Rheumatoid Arthritis Stratified Therapy Using Mendelian Randomization and a Pretraining Model

by

Yuqing Yan

,

You Wu

,

Yixuan Sun

,

Tian Wu

,

Haotian Zhu

,

Feiyang Xue

,

Zhanhui Yu

,

Shichao Liu

^*

and

Xiaohui Niu

^*

Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430074, China

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2025, 26(12), 5686; https://doi.org/10.3390/ijms26125686

Submission received: 1 April 2025 / Revised: 29 May 2025 / Accepted: 11 June 2025 / Published: 13 June 2025

(This article belongs to the Special Issue Genetic and Epigenetic Analyses in Cancer)

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Abstract

The prevalence of rheumatoid arthritis (RA) subtypes, including seropositive and seronegative, is influenced by lifestyle factors and exhibits high heterogeneity, resulting in reduced drug efficacy. This study aims to identify cytokines mediating the effects of different lifestyles on RA subtypes and to discover new drugs for personalized treatment. Mendelian randomization revealed that three cytokines (MIP1b, SCGFb, and TRAIL) partially mediated the effects of different lifestyles on RA overall or its subtypes. The pretrained model, i.e., DrugBAN, predicted the probability of 723,000 small molecule drugs binding to these three targets. In molecules with high binding rates, we calculated the structural similarity between known drugs for RA and other drugs to screen for new drugs, followed by molecular docking and molecular dynamics simulations for validation. The results indicate that these targets had promising binding affinity with known drugs and other drugs with high similarity. Our findings may guide therapeutic approaches for heterogeneous RA patients with specific lifestyle habits.

Keywords: rheumatoid arthritis subtypes; cytokines; pretraining model; drug prediction

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MDPI and ACS Style

Yan, Y.; Wu, Y.; Sun, Y.; Wu, T.; Zhu, H.; Xue, F.; Yu, Z.; Liu, S.; Niu, X. Identifying Targets and Drugs for Rheumatoid Arthritis Stratified Therapy Using Mendelian Randomization and a Pretraining Model. Int. J. Mol. Sci. 2025, 26, 5686. https://doi.org/10.3390/ijms26125686

AMA Style

Yan Y, Wu Y, Sun Y, Wu T, Zhu H, Xue F, Yu Z, Liu S, Niu X. Identifying Targets and Drugs for Rheumatoid Arthritis Stratified Therapy Using Mendelian Randomization and a Pretraining Model. International Journal of Molecular Sciences. 2025; 26(12):5686. https://doi.org/10.3390/ijms26125686

Chicago/Turabian Style

Yan, Yuqing, You Wu, Yixuan Sun, Tian Wu, Haotian Zhu, Feiyang Xue, Zhanhui Yu, Shichao Liu, and Xiaohui Niu. 2025. "Identifying Targets and Drugs for Rheumatoid Arthritis Stratified Therapy Using Mendelian Randomization and a Pretraining Model" International Journal of Molecular Sciences 26, no. 12: 5686. https://doi.org/10.3390/ijms26125686

APA Style

Yan, Y., Wu, Y., Sun, Y., Wu, T., Zhu, H., Xue, F., Yu, Z., Liu, S., & Niu, X. (2025). Identifying Targets and Drugs for Rheumatoid Arthritis Stratified Therapy Using Mendelian Randomization and a Pretraining Model. International Journal of Molecular Sciences, 26(12), 5686. https://doi.org/10.3390/ijms26125686

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Identifying Targets and Drugs for Rheumatoid Arthritis Stratified Therapy Using Mendelian Randomization and a Pretraining Model

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