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Pediatric obesity-related asthma is more severe and less responsive to medications than asthma in normal-weight children. Obese asthmatic children have nonatopic TH1-polarized systemic inflammation that correlates with pulmonary function deficits, but the pathways underlying TH1-polarized inflammation are not well understood.We compared the CD4+ T-cell transcriptome in obese children with asthma with that in normal-weight children with asthma to identify key differentially expressed genes associated with TH1-polarized inflammation.CD4+ T-cell transcriptome–wide differential gene expression was compared between 21 obese and 21 normal-weight children by using directional RNA sequencing. High-confidence differentially expressed genes were verified in the first cohort and validated in a second cohort of 20 children (10 obese and 10 normal-weight children) by using quantitative RT-PCR.Transcriptome-wide differential gene expression among obese asthmatic children was enriched for genes, includingVAV2,DOCK5,PAK3,PLD1,CDC42EP4, andCDC42PBB, which are associated with CDC42, a small guanosine triphosphate protein linked to T-cell activation. Upregulation ofMLK3 and PLD1, genes downstream of CDC42 in the mitogen-activated protein kinase and mammalian target of rapamycin pathways and the inverse correlation ofCDC42EP4andDOCK5transcript counts with FEV1/FVC ratio together support a role of CDC42 in the TH1 polarization and pulmonary function deficits found in patients with obesity-related asthma.Our study identifies the CDC42 pathway as a novel target that is upregulated in TH cells of obese asthmatic children, suggesting its role in nonatopic TH1-polarized systemic inflammation and pulmonary function deficits found in patients with pediatric obesity-related asthma.