Assessment of tenecteplase target-associated pathogenic mechanisms underlying depression in acute ischemic stroke patients: insights from artificial intelligence-driven multi-omics analysis and

Background: As a first-line treatment for acute ischemic stroke (AIS), tenecteplase (TNK) can cause adverse effects, such as depression, in AIS patients. Objective: This study aims to elucidate the TNK target-related pathogenic mechanisms underlying major depressive disorder (MDD) in AIS patients. Methods: By analyzing six public peripheral blood bulk datasets from AIS and MDD patients using integrative bioinformatics methods (limma, non-negative matrix factorization (NMF), and machine learning), we identified TNK target-associated molecular subgroups and diagnostic models for MDD and AIS patients, respectively. Next, a hub gene involved in the pathogenesis of both MDD and AIS was identified, and its corresponding molecular characteristics were analyzed in the peripheral blood bulk profiles of MDD and AIS patients. In addition, to gain a deeper understanding of the molecular implications of the hub gene involved in the pathogenesis of MDD in AIS, we performed disease ontology (DO) analysis and virtual cell knockout (KO) of the hub gene using public AIS mouse brain single-cell datasets. Furthermore, a deep learning pipeline (DrugReflector) model and molecular docking were used to identify MDD-preventive therapeutic agents for AIS patients based on MDD and AIS public blood bulk data. Finally, the expression pattern of the hub gene was also evaluated in MDD and AIS cell models. Results: Myeloperoxidase (MPO) can be considered an upregulated TNK target-associated gene involved in the pathogenesis of MDD in AIS patients, and BRD-K11973162 can be considered an MDD-preventive therapeutic candidate for AIS patients after TNK treatment. Conclusion: Our study is the first to identify MDD-associated diagnostic and therapeutic candidates for AIS patients after TNK treatment, providing a novel strategy for their clinical management.