Yu Haijia, Song Huihui, Li Jingchao, Cui Luqian, Dong Shujuan, Chu Yingjie, Qin Lijie
Department of Emergency, Henan Provincial People's Hospital, Zhengzhou, Henan, China.
Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou, Henan, China.
Sci Rep. 2024 Dec 28;14(1):30663. doi: 10.1038/s41598-024-75251-1.
There is growing evidence that programmed cell death plays a significant role in the pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH). Anoikis is a newly discovered type of programmed death and has garnered great attention. However, the precise involvement of Anoikis in the progression of CTEPH remains poorly understood. The goal of this study was to identify Anoikis-related genes (ARGs) and explore potential therapeutic drugs for CTEPH. Differentially expressed genes were identified by limma and weighted gene co-expression network analysis (WGCNA) packages, and functional analyses were conducted based on the differentially expressed genes. Subsequently, a combination of protein-protein interaction (PPI), Least Absolute Shrinkage and Selection Operator (LASSO), and Support Vector Machine Recursive Feature Elimination (SVM-RFE) methodologies was employed to screen hub genes associated with CTEPH, which were further verified by dataset GSE188938, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. CIBERSORT was utilized to evaluate the infiltration of immune cells and the relationship between infiltration-related immune cells and ARGs. Finally, targeted drug analysis and molecular docking were used to predict drugs targeting Anoikis process to treat CTEPH. Thirty-two differentially expressed genes related to Anoikis and CTEPH were screened through WGCNA analysis. Then, the key ARGs FASN, PLAUR, BCL2L1, HMOX1 and RHOB were screened by PPI, Lasso and SVM-RFE machine learning. Validation through dataset GSE188938, qRT-PCR, and Western blot analyses confirmed HMOX1 and PLAUR as powerful and promising biomarkers in CTEPH. In addition, CIBERSORT immunoinfiltration revealed that Mast_cells_activated and Neutrophils were involved in the pathological regulation of CTEPH. Correlation analysis indicated that HMOX1 was positively correlated with Neutrophils, while PLAUR was negatively correlated with Mast_cells_activated. Finally we used targeted drug analysis and molecular docking to identify that STANNSOPORFIN as a potential drug targeting HMOX1 for the treatment of CTEPH. HMOX1 and PLAUR emerge as potential biomarkers for CTEPH and may influence the development of CTEPH by regulating Anoikis. Mast_cells_activated and Neutrophils may be involved in Anoikis resistance in CTEPH patients, presenting novel insights into CTEPH therapeutic targets. STANNSOPORFIN is a potential agents targeting Anoikis process therapy for CTEPH.
越来越多的证据表明，程序性细胞死亡在慢性血栓栓塞性肺动脉高压（CTEPH）的发病机制中起重要作用。失巢凋亡是一种新发现的程序性死亡类型，已引起广泛关注。然而，失巢凋亡在CTEPH进展中的具体作用仍知之甚少。本研究的目的是鉴定与失巢凋亡相关的基因（ARGs），并探索CTEPH的潜在治疗药物。通过limma和加权基因共表达网络分析（WGCNA）软件包鉴定差异表达基因，并基于差异表达基因进行功能分析。随后，结合蛋白质-蛋白质相互作用（PPI）、最小绝对收缩和选择算子（LASSO）以及支持向量机递归特征消除（SVM-RFE）方法筛选与CTEPH相关的枢纽基因，并通过数据集GSE188938、定量实时聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法进行进一步验证。利用CIBERSORT评估免疫细胞的浸润情况以及浸润相关免疫细胞与ARGs之间的关系。最后，通过靶向药物分析和分子对接预测靶向失巢凋亡过程治疗CTEPH的药物。通过WGCNA分析筛选出32个与失巢凋亡和CTEPH相关的差异表达基因。然后，通过PPI、Lasso和SVM-RFE机器学习筛选出关键的ARGs FASN、PLAUR、BCL2L1、HMOX1和RHOB。通过数据集GSE188938、qRT-PCR和蛋白质免疫印迹分析验证，HMOX1和PLAUR是CTEPH中有潜力且有前景的生物标志物。此外，CIBERSORT免疫浸润分析显示，活化的肥大细胞和中性粒细胞参与CTEPH的病理调节。相关性分析表明，HMOX1与中性粒细胞呈正相关，而PLAUR与活化的肥大细胞呈负相关。最后，我们通过靶向药物分析和分子对接确定STANNSOPORFIN是一种潜在的靶向HMOX1治疗CTEPH的药物。HMOX1和PLAUR成为CTEPH的潜在生物标志物，可能通过调节失巢凋亡影响CTEPH的发展。活化的肥大细胞和中性粒细胞可能参与CTEPH患者的失巢凋亡抵抗，为CTEPH治疗靶点提供了新的见解。STANNSOPORFIN是一种潜在的靶向失巢凋亡过程治疗CTEPH的药物。
