Decoding Heart Failure-Associated Transcriptomic Signatures via RNA Sequencing and Structure Based Docking Studies of Flavone Derivatives Targeting AXL Kinase

Heart failure (HF) is prevalent cardiovascular diseases that significantly impact the health of patients. Although efforts have been made to clarify its pathology, the underlying molecular mechanisms of HF are still not clear. We aimed to explore the molecular mechanism and identify some new diagnostic or therapeutic targets for HF treatment via bioinformatics analysis. The RNA-sequencing dataset GSE262824 was downloaded from the Gene Expression Omnibus (GEO) database to identify biomarkers for effective HF diagnosis and therapy. The differentially expressed genes (DEGs) were identified by DESeq2, and function enrichment analyses were conducted using the Gene Ontology (GO) and REACTOME. The Intact interactome database and Cytoscape software were used to construct and analyze the protein-protein interaction network (PPI) and its modules. miRNA-hub gene regulatory network and TF-hub gene regulatory network were performed in miRNet and NetworkAnalyst. Besides, the identified hub genes were submitted to the DrugBank database to find relevant therapeutic drug molecules from drug-hub gene interaction network. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the predictive value of hub genes. Finally, AXL receptor tyrosine kinase was considered for subsequent molecular docking because of its frequent appearance throughout the analysis. AXL receptor tyrosine kinase was docked with the 23 phytochemicals (flavone derivatives). ADMET properties were predicted phytochemicals. We identified 958 DEGs, consisting of 479 up regulated genes and 479 down regulated genes. GO and pathway enrichment analysis showed that the DEGs were mainly focused on response to stimulus, multicellular organismal process, immune system and SLC-mediated transmembrane transport. PPI analysis showed two important modules and hub genes: RIN3, H2BC5, AQP3, FPR1, PLEC, VCAM1, SLC7A1, FOS, PRG2 and PIK3R1. hsa-miR-125a-3p, hsa-miR-484, EWSR1, NFE2L2, Epinastine and Risperidone are the most common miRNAs, TFs and drug molecules in regulating hub genes, respectively. In the ROC curve analysis, all hub genes showed good efficiency in helping distinguish HF from normal controls. Molecular docking analysis showed that compound 1v bound to AXL kinase with highest binding affinity of -8.1 kcal/mol. We have also found that the selected four compounds displayed favorable ADMET properties. In summary, identification of the hub genes, miRNAs and TFs in our research enables us to elaborate the molecular mechanisms underlying the genesis and progression of HF and identify potential targets for the diagnosis and treatment of HF.