Sun, B.; Lu, Y.; Liu, W.; Wang, C.

Antiphospholipid syndrome (APS) lacks targeted therapies beyond anticoagulation, and its molecular heterogeneity remains poorly characterized. We employed an integrative systems pharmacology approach combining weighted gene co-expression network analysis (WGCNA), single-cell RNA sequencing, Connectivity Map (CMap) screening, and molecular docking to identify druggable targets in APS. WGCNA of bulk RNA-seq data from neutrophils (n = 18) and whole blood (n = 88) identified two disease-associated modules: ME10 (176 genes, r = 0.77, interferon-I signaling) and ME2 (3409 genes, r = 0.79, degranulation/innate activation). Single-cell analysis of 26,936 B cells revealed transitional B cells with elevated ME2 scores and aberrant SPI1 expression, suggesting myeloid-like transcriptional reprogramming. CMap analysis ranked chloroquine, a first-line APS therapy, among top ME2 candidates (NCS = -2.07), validating the computational approach. DrugBank mapping identified 14 FDA-approved drugs targeting module genes, and a 3-gene machine learning signature (CORO1A, ANKRD22, IFITM1) achieved cross-tissue validation AUC of 0.802. External validation confirmed ME2 pathway modulation by NAPc2 intervention and cross-tissue module conservation in platelets. Patient-level ME10 x ME2 stratification revealed four molecular subtypes with distinct pathway activation profiles. This framework nominates druggable targets across both IFN-I and degranulation pathways, providing a foundation for pathway-guided precision medicine in APS.