Zhao Xueling, He Menghao, Zhou Desheng, Li Zhong, Liu Lijuan, Yang Renyi, Zhu Xinhua, Gong Cuilan, Yan Siyang
The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, 410007, People's Republic of China.
Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People's Republic of China.
BMC Neurol. 2025 Jul 1;25(1):255. doi: 10.1186/s12883-025-04239-9.
Stroke is a leading cause of death and disability worldwide, yet its treatment still faces significant challenges. Mendelian randomization (MR) has been widely used to discover new biomarkers and therapeutic targets. This study aimed to identify therapeutic targets for stroke within the plasma proteome range using MR.
We conducted a two-sample MR study, evaluating the causal relationships between 2,940 plasma proteins from the UK Biobank-Proteome-wide Association Study (UKB-PPP) and stroke, with further validation in 4,907 plasma proteins from Iceland. Subsequently, drug target proteins were determined using Bayesian colocalization, Summary data-based Mendelian randomization (SMR), and protein-protein interaction (PPI) network construction to validate the role of selected disease-associated proteins.
Preliminary MR analysis identified 11 proteins (LPA, FURIN, MST1, FKBPL, SH2B3, MMP12, F11, ITGAV, DDHD2, VSIR and GAS6) significantly associated with stroke or stroke subtypes. Through SMR and colocalization analysis, 4 potential drug target proteins were identified: FURIN as a potential drug target for stroke and any ischemic stroke, F11 as a potential drug target for cardioembolic stroke, DDHD2 and VSIR as potential drug targets for small vessel stroke. It is worth noting that F11 is currently being used in the development of multiple drugs, FURIN is not only associated with stroke but also appears to have abnormal expression in several cardiovascular diseases. Although research on DDHD2 and VSIR in the context of stroke is relatively limited, current findings indicate that DDHD2 is related to synaptic plasticity, while VSIR is associated with microglia and immune responses.
This study found that the plasma proteins FURIN, F11, DDHD2, and VSIR show promise as potential therapeutic targets for stroke and its subtypes, providing genetic evidence to support precision drug development and insights into the underlying pathological mechanisms of stroke.
Not applicable.
中风是全球死亡和残疾的主要原因，但其治疗仍面临重大挑战。孟德尔随机化（MR）已被广泛用于发现新的生物标志物和治疗靶点。本研究旨在利用MR在血浆蛋白质组范围内确定中风的治疗靶点。
我们进行了一项两样本MR研究，评估了来自英国生物银行蛋白质组全关联研究（UKB-PPP）的2940种血浆蛋白与中风之间的因果关系，并在冰岛的4907种血浆蛋白中进行了进一步验证。随后，使用贝叶斯共定位、基于汇总数据的孟德尔随机化（SMR）和蛋白质-蛋白质相互作用（PPI）网络构建来确定药物靶蛋白，以验证所选疾病相关蛋白的作用。
初步MR分析确定了11种蛋白（LPA、FURIN、MST1、FKBPL、SH2B3、MMP12、F11、ITGAV、DDHD2、VSIR和GAS6）与中风或中风亚型显著相关。通过SMR和共定位分析，确定了4种潜在的药物靶蛋白：FURIN作为中风和任何缺血性中风的潜在药物靶点，F11作为心源性栓塞性中风的潜在药物靶点，DDHD2和VSIR作为小血管中风的潜在药物靶点。值得注意的是，F11目前正在用于多种药物的研发，FURIN不仅与中风有关，而且在几种心血管疾病中似乎也有异常表达。虽然关于DDHD2和VSIR在中风背景下的研究相对有限，但目前的研究结果表明，DDHD2与突触可塑性有关，而VSIR与小胶质细胞和免疫反应有关。
本研究发现，血浆蛋白FURIN、F11、DDHD2和VSIR有望成为中风及其亚型的潜在治疗靶点，为支持精准药物开发提供了遗传学证据，并深入了解了中风的潜在病理机制。
不适用。
