Integrative network toxicology and clinical validation identify CD4, PTGS2, and KDR as candidate targets of nicotine in infantile hemangioma.
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Infantile hemangioma (IH) is the most common benign vascular tumor of infancy. Perinatal tobacco smoke exposure has been associated with pediatric benign tumors, but a specific molecular link between nicotine and IH has not been established. We aimed to identify and validate candidate targets of nicotine in IH. Age-stratified differentially expressed genes (6, 12, and 24 months) from GSE127487 were intersected with IH- and nicotine-related targets and prioritized by network analysis, followed by enrichment analysis, immune deconvolution, and molecular docking, with tissue validation and machine-learning screening of a clinical cohort (77 patients, 50 controls). CD4, PTGS2, and KDR were core targets shared across age groups, whereas EGFR, PPARG, TLR4, and ACE were stage-restricted; enrichment converged on PI3K-Akt, MAPK, HIF-1, and VEGF signaling. Nicotine showed computationally plausible docking to KDR (-6.91 kcal/mol) and PTGS2 (-6.39 kcal/mol). CD4 and PTGS2 proteins were markedly upregulated in IH lesions, with KDR showing a concordant upward trend (paired t-test: P < 0.001, P < 0.001, and P = 0.062, respectively). Single-cell re-analysis placed KDR in GLUT1-positive lesional endothelium and CD4 transcripts mainly in myeloid and mural cells. A four-indicator blood signature (globulin, mean platelet volume, platelet distribution width, and total protein; AUC 0.942, 95 % CI 0.859-1.000) reflected the associated immune-inflammation state. These hypothesis-generating results nominate a CD4-, PTGS2-, and KDR-centered network converging on angiogenic and inflammatory signaling as a candidate route through which nicotine may act in IH. These candidate targets and the blood signature require external-cohort and mechanistic validation.