Multi-omics analysis of immunometabolic mechanisms linking IL-33 with asthma control in children

Background : Interleukin-33 (IL-33) is a key alarmin in paediatric asthma and is clinically associated with poor disease control and type-2 inflammation, but how IL-33 links membrane lipid remodelling, vesicular/signalling pathways and downstream immune activation in children remains unclear. We aimed to define lipidomic and proteomic signatures associated with circulating IL-33 and to relate these molecular features to asthma control and atopic burden. Methods: We prospectively enrolled 60 children with physician-diagnosed asthma and stratified them into high- and low-IL-33 groups by serum IL-33. Untargeted serum lipidomics (n = 6 vs. 6) and label-free serum proteomics (n = 6 vs. 6) were performed on matched subsets. Differential features were identified with Benjamini–Hochberg FDR control, followed by KEGG enrichment and cross-omics integration. Associations with Asthma Control Questionnaire (ACQ) scores, total IgE and blood eosinophil percentages were assessed by Spearman correlation. A targeted qPCR panel (RELA, NFKBIA, GATA3, TBX21, PRKACA, STAM2, SPHK1, LIPE, with ADCY6, S1PR1 and ACAA1 as supplements) was used to validate the intersecting NF-κB/Th, cAMP and endocytic pathways. Results: Children in the high-IL-33 group had worse asthma control and higher allergic indices than those in the low-IL-33 group (ACQ ↑, total IgE ↑, eosinophils ↑). Lipidomics revealed a selective membrane-oriented remodelling pattern in the high-IL-33 group, characterised by increases in PC, PE and CL and a relative depletion of sphingomyelin species, with enrichment in NF-κB signalling, Th1/Th2/Th17 differentiation and regulation of lipolysis. Proteomics showed concomitant up-regulation of endocytosis, ESCRT/vesicular transport, actin/cytoskeleton organisation, cAMP and sphingolipid signalling pathways. Cross-layer pathway overlap and correlation matrices indicated that lipid and protein changes converged on an IL-33–responsive immune axis that requires both a permissive, reconfigured membrane platform and an activated receptor-processing apparatus. qPCR findings were directionally consistent with the multi-omics results, confirming transcriptional activation of NF-κB/Th-skewing (RELA↑, GATA3↑, NFKBIA↓), cAMP/ADCY6–PRKACA signalling and vesicle-related genes (STAM2↑), which in turn correlated with ACQ, IgE and eosinophilia. Conclusions: Our data support an IL-33–lipid–transport axis in paediatric asthma, in which IL-33 elevation drives membrane-lipid remodelling (PC/PE/CL↑, SM↓) and parallel activation of endocytic/cAMP machinery, collectively funnelling into NF-κB- and Th-centred inflammatory programmes that associate with poor asthma control. This composite lipid–protein–transcript fingerprint may serve as a stratification marker for IL-33-high endotypes and highlights IL-33/ST2 together with lipid-metabolic and cAMP-modulating targets as candidate therapeutic nodes.