Multi-omics insights into immune dysregulation and candidate biological programs in kawasaki disease: toward precision immunomodulation

Kawasaki disease (KD) is an immune-mediated pediatric vasculitis characterized by dynamic interactions among genetic susceptibility, innate and adaptive immune activation, endothelial dysfunction, and vascular remodeling. Although intravenous immunoglobulin (IVIG) therapy substantially reduces coronary complications, 10%–20% of patients show persistent or recurrent fever after initial IVIG treatment, and reliable clinically validated molecular approaches for diagnosis, treatment-response prediction, and coronary-risk stratification remain unavailable. Recent advances in multi-omics technologies, including genomics, epigenomics, transcriptomics, single-cell sequencing, proteomics, metabolomics, and microbiome profiling, have expanded our understanding of KD-associated immune dysregulation. However, the clinical interpretation of these molecular findings remains challenging because of limited cohort sizes, heterogeneous control populations, treatment-related confounding, and insufficient external validation. In this review, we integrate evidence across multiple molecular layers and propose a framework in which current KD multi-omics findings converge into candidate biological programs rather than fixed molecular subtypes. These programs may represent temporally dynamic biological states along a shared inflammatory trajectory, influenced by disease phase, cellular composition, genetic background, and treatment exposure. Synthesized from convergent multi-omics evidence rather than derived from formal molecular classification, these candidate biological programs include myeloid inflammatory activation characterized by S100A8/A9 and IL-1/NF- κ B signaling, interferon-associated immune responses, and vascular injury/remodeling responses involving endothelial activation and extracellular matrix regulation. Current evidence supports biologically meaningful molecular programs that may contribute to clinical heterogeneity, but prospective validation is required before molecular signatures can be applied as clinical classifiers or treatment-selection tools. Integrating multi-omics approaches with functional validation, longitudinal sampling, and multicenter studies may facilitate the development of precision immunomodulation strategies for Kawasaki disease.