{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T18:19:38Z","timestamp":1787768378390,"version":"build-2784847793"},"reference-count":71,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>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\u2009=\u200918), with module preservation confirmed in whole blood (n\u2009=\u200988), identified two disease-associated modules: ME10 (176 genes, r\u2009=\u20090.77, interferon-I signaling) and ME2 (3409 genes, r\u2009=\u20090.79, 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 \u2014 a 4-aminoquinoline antimalarial closely related to hydroxychloroquine, which is recommended as adjunctive therapy in APS \u2014 among top ME2 candidates (NCS\u2009=\u2009\u22122.07), 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.<\/jats:p>","DOI":"10.1371\/journal.pone.0349155","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T17:36:21Z","timestamp":1787765781000},"page":"e0349155","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systems pharmacology reveals type I interferon and myeloid-like B cell reprogramming as candidate druggable axes in antiphospholipid 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