Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang, China.
Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
Sci Rep. 2024 Nov 27;14(1):29436. doi: 10.1038/s41598-024-79897-9.
Monkeypox (Mpox) is a growing public health concern, with complex interactions within host systems contributing to its impact. This study employs multi-omics approaches to uncover therapeutic targets and potential drug repurposing opportunities to better understand Mpox's molecular pathogenesis. We developed an in silico host-pathogen interaction (HPI) network and applied weighted gene co-expression network analysis (WGCNA) to explore interactions between Mpox and host proteins. Subtype-specific host-pathogen protein-protein interaction networks were constructed, and key modules from the HPI and WGCNA were integrated to identify significant host proteins. To predict upstream signaling pathways and transcription factors, we used eXpression2Kinases and ChIP-X Enrichment Analysis. The multi-Steiner trees method was applied to compare our findings with those from FDA-approved antiviral drugs. Analysis of 55 differentially expressed genes in Mpox infection revealed 11 kinases and 15 transcription factors as key regulators. We identified 16 potential drug targets, categorized into 8 proviral genes (ESR2, ERK1, ERK2, P38, JNK1, CDK4, GSK3B, STAT3) designated for inhibition, and 8 antiviral genes (IKKA, HDAC1, HIPK2, TF65, CSK21, HIPK2, ESR2, GSK3B) designated for activation. Proviral genes are involved in the AKT, Wnt, and STAT3 pathways, while antiviral genes impact the AP-1, NF-κB, apoptosis, and IFN pathways. Promising FDA-approved candidates were identified, including kinase inhibitors, steroid hormone receptor agonists, STAT3 inhibitors, and notably Niclosamide. This study enhances our understanding of Mpox by identifying key therapeutic targets and potential repurposable drugs, providing a valuable framework for developing new treatments.
猴痘（Mpox）是一个日益严重的公共卫生关注点，宿主系统内的复杂相互作用导致了其影响。本研究采用多组学方法来揭示治疗靶点和潜在的药物再利用机会，以更好地理解 Mpox 的分子发病机制。我们构建了一个计算宿主-病原体相互作用（HPI）网络，并应用加权基因共表达网络分析（WGCNA）来探索 Mpox 与宿主蛋白之间的相互作用。构建了亚型特异性的宿主-病原体蛋白-蛋白相互作用网络，并整合 HPI 和 WGCNA 的关键模块来鉴定显著的宿主蛋白。为了预测上游信号通路和转录因子，我们使用了 eXpression2Kinases 和 ChIP-X 富集分析。多 Steiner 树方法用于比较我们的发现与 FDA 批准的抗病毒药物的发现。对 Mpox 感染中 55 个差异表达基因的分析揭示了 11 个激酶和 15 个转录因子作为关键调节剂。我们鉴定了 16 个潜在的药物靶点，分为 8 个前病毒基因（ESR2、ERK1、ERK2、P38、JNK1、CDK4、GSK3B、STAT3）和 8 个抗病毒基因（IKKA、HDAC1、HIPK2、TF65、CSK21、HIPK2、ESR2、GSK3B）。前病毒基因参与 AKT、Wnt 和 STAT3 通路，而抗病毒基因影响 AP-1、NF-κB、凋亡和 IFN 通路。确定了一些有前景的 FDA 批准候选药物，包括激酶抑制剂、甾体激素受体激动剂、STAT3 抑制剂，特别是尼拉帕尼。本研究通过鉴定关键治疗靶点和潜在的再利用药物，增强了我们对 Mpox 的理解，为开发新的治疗方法提供了有价值的框架。
