Objectives: To explore the molecular mechanisms underlying cystoid macular edema (CME) through protein-protein interaction (PPI) network analysis, identifying key regulatory proteins, functional modules, and enriched biological pathways relevant to its pathogenesis.
Methods: A curated list of 18 CME-associated human proteins was compiled through a literature review, including inflammatory cytokines, angiogenic factors, and regulators of vascular permeability. High-confidence PPI data were obtained from the STRING database (confidence score ≥ 0.700) and visualized as an undirected graph using NetworkX in Python. Centrality metrics (degree, betweenness, closeness, eigenvector), Louvain modularity analysis, and functional enrichment (GO: BP, KEGG, Reactome) were performed using GSEAPY and Enrichr to identify topologically and biologically important nodes and clusters.
Results: The final network consisted of 91 nodes and 217 edges, with a graph density of 0.0505 and an average clustering coefficient of 0.0554. ANGPT2, FLT1, KDR, TNF, and VEGFA appeared as central hub proteins across multiple centrality measures. Louvain clustering identified eight distinct functional communities, including inflammatory mediators, angiogenic signaling components, and tight junction regulators. Enrichment analyses showed significant involvement of cytokine-mediated signaling, endothelial cell migration, the AGE-RAGE pathway, TNF signaling, and interleukin-4/10/13 signaling, highlighting the dual roles of angiogenesis and inflammation in CME.
Discussion: The findings of this study highlight the intricate network of molecular mechanisms underlying cystoid macular edema (CME), with particular emphasis on angiogenesis, inflammation, and vascular permeability. The identification of key regulatory proteins such as ANGPT2, FLT1, and TNF underscores the complexity of CME pathogenesis, which involves both vascular and inflammatory pathways.
Conclusions: CME is driven by a complex, modular molecular network involving inflammation, vascular remodeling, and cytokine signaling. ANGPT2, FLT1, TNF, and IL6 are key regulatory proteins and potential therapeutic targets. This systems biology approach offers a comprehensive framework for discovering new insights and guiding personalized treatment strategies in CME.
Keywords: AKT1 = AKT Serine/Threonine Kinase 1; AKT2 = AKT Serine/Threonine Kinase 2; ANGPT2; ANGPT2 = Angiopoietin-2; AQP4 = Aquaporin 4; Apoptosis Regulator; BAX = BCL2 Associated X; BCL2 = BCL2 Apoptosis Regulator; CASP3 = Caspase 3; CASP9 = Caspase 9; CCL2 = C-C Motif Chemokine Ligand 2 (MCP-1); CCL5 = C-C Motif Chemokine Ligand 5 (RANTES); CCR2 = C-C Motif Chemokine Receptor 2; CDH5 = Cadherin 5 (VE-Cadherin); CLDN5 = Claudin 5; CXCL10 = C-X-C Motif Chemokine Ligand 10; CXCL8 = C-X-C Motif Chemokine Ligand 8 (IL-8); CXCL9 = C-X-C Motif Chemokine Ligand 9; CYBA = Cytochrome B-245 Alpha Chain; EDN1 = Endothelin 1; EPO = Erythropoietin; ERK1 = Extracellular Signal-Regulated Kinase 1 (MAPK3); ERK2 = Extracellular Signal-Regulated Kinase 2 (MAPK1); FGF1 = Fibroblast Growth Factor 1; FGF2 = Fibroblast Growth Factor 2; FGFR1 = Fibroblast Growth Factor Receptor 1; FGFR2 = Fibroblast Growth Factor Receptor 2; FLT1 = Fms Related Tyrosine Kinase 1 (VEGFR-1); FOXO1 = Forkhead Box O1; HIF1A = Hypoxia Inducible Factor 1 Subunit Alpha; HMOX1 = Heme Oxygenase 1; ICAM1 = Intercellular Adhesion Molecule 1; ICAM2 = Intercellular Adhesion Molecule 2; IFNG = Interferon Gamma; IL10 = Interleukin 10; IL10RA = Interleukin 10 Receptor Subunit Alpha; IL13 = Interleukin 13; IL13RA1 = Interleukin 13 Receptor Subunit Alpha 1; IL17A = Interleukin 17A; IL18 = Interleukin 18; IL1A = Interleukin 1 Alpha; IL1B = Interleukin 1 Beta; IL4 = Interleukin 4; IL4R = Interleukin 4 Receptor; IL6 = Interleukin 6; IL6R = Interleukin 6 Receptor; ITGAM = Integrin Subunit Alpha M; ITGB2 = Integrin Subunit Beta 2; JAK1 = Janus Kinase 1; JAK2 = Janus Kinase 2; JAM2 = Junctional Adhesion Molecule 2; KDR = Kinase Insert Domain Receptor (VEGFR-2); MAP2K1 = Mitogen-Activated Protein Kinase Kinase 1; MAPK1 = Mitogen-Activated Protein Kinase 1 (ERK2); MAPK3 = Mitogen-Activated Protein Kinase 3 (ERK1); MAPK8 = Mitogen-Activated Protein Kinase 8 (JNK1); MMP1 = Matrix Metallopeptidase 1; MMP2 = Matrix Metallopeptidase 2; MMP3 = Matrix Metallopeptidase 3; MMP7 = Matrix Metallopeptidase 7; MMP9 = Matrix Metallopeptidase 9; Mitochondrial; NF-κB Subunit; NFKB1 = Nuclear Factor Kappa B Subunit 1; NFKBIA = NFKB Inhibitor Alpha; NOS2 = Nitric Oxide Synthase 2 (Inducible); NOS3 = Nitric Oxide Synthase 3 (Endothelial); NOX4 = NADPH Oxidase 4; OCLN = Occludin; PDGFB = Platelet-Derived Growth Factor Subunit B; PECAM1 = Platelet and Endothelial Cell Adhesion Molecule 1; PI3KCA = Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha; PLAT = Plasminogen Activator; PLAU = Plasminogen Activator; PRKCA = Protein Kinase C Alpha; PRKCB = Protein Kinase C Beta; PTGS2 = Prostaglandin-Endoperoxide Synthase 2 (COX-2); RAC1 = Rac Family Small GTPase 1; RELA = RELA Proto-Oncogene; S1PR1 = Sphingosine-1-Phosphate Receptor 1; SELE = Selectin E; SELP = Selectin P; SERPINE1 = Serpin Family E Member 1 (PAI-1); SOCS3 = Suppressor of Cytokine Signaling 3; SOD2 = Superoxide Dismutase 2; STAT3 = Signal Transducer and Activator of Transcription 3; TGFB1 = Transforming Growth Factor Beta 1; TGFBR1 = Transforming Growth Factor Beta Receptor 1; TGFBR2 = Transforming Growth Factor Beta Receptor 2; TIMP1 = TIMP Metallopeptidase Inhibitor 1; TIMP2 = TIMP Metallopeptidase Inhibitor 2; TNF = Tumor Necrosis Factor; TYK2 = Tyrosine Kinase 2; Tissue Type; Urokinase; VCAM1 = Vascular Cell Adhesion Molecule 1; VEGFA; VEGFA = Vascular Endothelial Growth Factor A; angiogenesis; cystoid macular edema; enrichment analysis; inflammation; protein-protein interaction network; systems biology.
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