An Iron–Complement Network Model of Thromboinflammation and Humoral Immune Remodeling in Severe COVID-19

Severe COVID-19 is characterized by profound thromboinflammatory and immune disturbances, but the network-level relationships among complement–coagulation dysregulation, humoral immune remodeling, and iron-associated immune regulation remain incompletely understood. Here, we performed integrative proteomic and transcriptomic analyses across peripheral blood and lung microenvironments using weighted gene co-expression network analysis (WGCNA), differential network analysis (DiNA), and immune deconvolution. Proteomic network analysis identified a disease-associated module enriched in complement activation, coagulation cascades, platelet degranulation, and acute inflammatory responses. Hub proteins, including C9, LBP, vWF, and F11, were prioritized based on module association and intramodular connectivity. Notably, C9 and LBP were repeatedly identified across WGCNA, DiNA, and differential expression analyses, underscoring their robust association with severe COVID-19-associated molecular network remodeling. Transcriptomic and CIBERSORTx-based immune deconvolution analyses showed altered immune-cell composition in blood and lung tissues, including B-cell and plasma-cell-associated changes. Notably, TFRC displayed cell-type-associated expression changes in naïve B cells and plasma cells, suggesting a potential link between iron-associated immune regulation and humoral immune remodeling. Collectively, these computational findings highlight coordinated complement–coagulation dysregulation, humoral immune remodeling, and TFRC-associated iron-related immune alterations in severe COVID-19, and prioritize TFRC, C9, and LBP as candidate molecular indicators requiring further experimental and clinical validation.