Systems pharmacology reveals type I interferon and myeloid-like B cell reprogramming as candidate druggable axes in antiphospholipid syndrome.

Antiphospholipid syndrome (APS) lacks disease-modifying targeted therapies, 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 prioritize candidate therapeutic targets in APS. WGCNA of purified-neutrophil bulk RNA-seq (n = 18), with module preservation confirmed in 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 4-aminoquinoline antimalarial closely related to hydroxychloroquine, which is recommended as adjunctive therapy in APS - among top ME2 candidates (NCS = -2.07), supporting the biological relevance of the screen. 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 datasets supported 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 prioritizes candidate targets across both IFN-I and degranulation pathways, generating hypotheses for pathway-guided therapeutic development that require experimental and clinical validation.