Therapeutic gene targets and epigenetic modifications in rheumatoid arthritis: Insights from MTX, JAK inhibitors, and LLDT-8

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports Pub Date : 2025-05-05 DOI:10.1016/j.bbrep.2025.102038

Jianan Zhao , Yunshen Li , Runrun Zhang , Yu Shan , Chenyang Song , Yaxin Cheng , Yiming Shi , Yixin Zheng , Fuyu Zhao , Junyu Fan , Cen Chang , Yuejuan Zheng , Dongyi He

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引用次数: 0

Abstract

Objective

This study investigates therapeutic gene targets and their epigenetic modifications in rheumatoid arthritis (RA), focusing on the molecular effects of methotrexate (MTX), Janus kinase (JAK) inhibitors, and (5R)-5-hydroxytriptolide (LLDT-8) on fibroblast-like synoviocytes (FLS).

Methods

Primary FLS were isolated from synovial tissues of RA and osteoarthritis (OA) patients and treated with MTX, JAK inhibitors, and LLDT-8. RNA sequencing identified differentially expressed genes (DEGs) under each treatment. The intersection of differentially expressed genes with trend analysis identified as potential drug target genes. Functional enrichment analyses were performed to explore associated pathways. Methylation changes in key genes were examined using the GEO database (GSE46364), and clinical relevance was evaluated using RA patient data from the PEAC database.

Results

Compared to the osteoarthritis FLS group, the RA FLS group showed significant differences in 5095 genes (3300 upregulated and 1795 downregulated). After JAK inhibitor treatment, 3795 significant differential genes were identified in RA FLS (1733 upregulated and 2062 downregulated). MTX treatment resulted in 3195 significant differential genes (2171 upregulated and 1023 downregulated), while LLDT-8 treatment revealed 12,993 significant differential genes (7801 upregulated and 5192 downregulated). Following trend analysis and de-duplication, we identified 45 important drug target genes that exhibited significant correlations with common clinical indices in RA patients. Among these, GALNT9 and CCNF showed notable alterations in both methylation and expression levels, suggesting potential roles in RA pathogenesis and drug response. Functional enrichment highlighted critical pathways, including cell cycle, FoxO, and p53 signaling, which are implicated in FLS regulation and RA progression.

Conclusion

This study highlights therapeutic gene targets and their epigenetic modifications as potential mechanisms underlying the effects of MTX, JAK inhibitors, and LLDT-8 in RA treatment. GALNT9 and CCNF emerge as promising candidates for further exploration in targeted therapeutic strategies.

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类风湿性关节炎的治疗性基因靶点和表观遗传修饰：来自MTX、JAK抑制剂和LLDT-8的见解

目的研究类风湿关节炎（RA）的治疗性基因靶点及其表观遗传修饰，重点研究甲氨蝶呤（MTX）、Janus激酶（JAK）抑制剂和(5R)-5-羟基雷公素（LLDT-8）对成纤维细胞样滑膜细胞（FLS）的分子作用。方法从RA和骨关节炎（OA）患者的滑膜组织中分离原发性FLS，用MTX、JAK抑制剂和LLDT-8治疗。RNA测序鉴定了不同处理下的差异表达基因（DEGs）。差异表达基因与趋势分析的交集被确定为潜在的药物靶基因。通过功能富集分析来探索相关通路。使用GEO数据库（GSE46364）检测关键基因的甲基化变化，并使用PEAC数据库中的RA患者数据评估临床相关性。结果与骨关节炎FLS组相比，RA FLS组有5095个基因（上调3300个，下调1795个）存在显著差异。经JAK抑制剂治疗后，在RA FLS中鉴定出3795个显著差异基因（上调1733个，下调2062个）。MTX处理导致3195个显著差异基因（2171个上调，1023个下调），而LLDT-8处理显示12993个显著差异基因（7801个上调，5192个下调）。通过趋势分析和去重复，我们确定了45个重要的药物靶基因，这些基因与RA患者的常见临床指标有显著相关性。其中，GALNT9和CCNF的甲基化和表达水平均有显著变化，提示在RA发病机制和药物反应中可能发挥作用。功能富集强调了关键途径，包括细胞周期、FoxO和p53信号，它们与FLS调节和RA进展有关。结论本研究强调了MTX、JAK抑制剂和LLDT-8治疗类风湿性关节炎的潜在机制，即治疗性基因靶点及其表观遗传修饰。GALNT9和CCNF是进一步探索靶向治疗策略的有希望的候选者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemistry and Biophysics Reports Biochemistry, Genetics and Molecular Biology-Biophysics

CiteScore

4.60

自引率

0.00%

发文量

191

审稿时长

59 days

期刊介绍： Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.