Uncovering the Therapeutic Target and Molecular Mechanism of Upadacitinib on Sjogren's Syndrome.

IF 2.3 Q3 ENGINEERING, BIOMEDICAL Biomedical Engineering and Computational Biology Pub Date : 2024-10-23 eCollection Date: 2024-01-01 DOI:10.1177/11795972241293519
Youguo Yang, Yuan Liu, Xiaofen Li, Yongping Zeng, Weiqian He, Juan Zhou
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Abstract

Objective: Upadacitinib, a selective Janus associated kinase 1 (JAK-1) inhibitor, can be prescribed particularly for the clinical treatment with Crohn's disease or rheumatoid arthritis. It is clinically observed that upadacitinib has been found with potential therapeutic effectiveness on Sjogren's syndrome (SS). However, the anti-SS targets and mechanisms involved in upadacitinib treatment remain uninvestigated.

Materials and methods: Thus, this study was designed to identify therapeutic targets and mechanisms of upadacitinib for treating SS through conducting network pharmacology and molecular docking analyses.

Results: In total, we identified 298 upadacitinib-related target genes, 1339 SS-related targets before collecting 56 overlapped target genes and 12 hub target genes. Upadacitinib largely exerted the critical biological processes including regulation of microenvironment homeostasis, inflammatory response, and cell apoptosis, and largely acted on pivotal molecular mechanisms including hypoxia-inducible factor 1 (HIF-1) signaling pathway, apoptosis pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, or Th17 cell differentiation pathway. Molecular docking data suggested that upadacitinib exhibited the high affinities with signal transducer and activator of transcription 3 (STAT3), HIF1A, poly(ADP-ribose) polymerase 1 (PARP1) target proteins, in which the structural interactions between upadacitinib and STAT3, HIF1A, PARP1 showed potential therapeutic activities against SS.

Conclusion: In conclusion, upadacitinib possesses the bright anti-inflammatory and anti-apoptotic activities on SS, and this study can provide a theoretical basis for clinical therapy of SS using upadacitinib.

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揭示 Upadacitinib 对 Sjogren's 综合征的治疗靶点和分子机制。
目的:乌达帕替尼是一种选择性 Janus 相关激酶 1(JAK-1)抑制剂,特别适用于克罗恩病或类风湿性关节炎的临床治疗。临床观察发现,奥达帕替尼对 Sjogren's 综合征(SS)具有潜在疗效。然而,奥达替尼治疗SS的抗SS靶点和机制仍未得到研究:因此,本研究旨在通过开展网络药理学和分子对接分析,确定乌达替尼治疗SS的治疗靶点和机制:结果:我们共发现了 298 个达达替尼相关靶基因、1339 个 SS 相关靶基因,然后收集了 56 个重叠靶基因和 12 个枢纽靶基因。奥达替尼在很大程度上影响了微环境稳态调节、炎症反应和细胞凋亡等关键生物学过程,并在很大程度上作用于缺氧诱导因子1(HIF-1)信号通路、细胞凋亡通路、磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/Akt)信号通路或Th17细胞分化通路等关键分子机制。分子对接数据表明,乌达替尼与信号转导和转录激活因子3(STAT3)、HIF1A、聚(ADP-核糖)聚合酶1(PARP1)靶蛋白具有高亲和力,其中乌达替尼与STAT3、HIF1A、PARP1之间的结构相互作用显示出对SS的潜在治疗活性:总之,奥达替尼对SS具有明显的抗炎和抗凋亡活性,该研究可为奥达替尼对SS的临床治疗提供理论依据。
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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