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Research Article: Implications of isonicotinylation-associated patterns in NK cells in the pathogenesis of Kawasaki disease: evidence from artificial intelligence-driven multi-omics and clinical validation

Date Published: 2026-07-22

Abstract:
Kawasaki disease (KD) is a systemic vasculitis of childhood driven by aberrant immune activation. Natural killer (NK) cell dysregulation plays a critical role, but its upstream molecular mechanisms remain unclear. Isonicotinylation (Kinic), a novel lysine acylation acting as a metabolic sensor, represents an unexplored regulatory layer in KD. We employed an artificial intelligence (AI)-driven multi-omics framework. Limma differential expression analysis on GSE68004 (KD patient bulk profile) identified Kinic-related differentially expressed genes. Weighted gene co-expression network analysis (WGCNA) and CIBERSORT on GSE18606 (KD patient bulk profile) delineated an NK cell-correlated module. Their intersection defined Kinic- and NK (KN)-related signature, which was used to construct a diagnostic model via an explainable machine learning pipeline on KD patient bulk profiles (GSE73463, GSE73462, and GSE63881). The central hub gene was validated using KD patient single-cell RNA-sequencing (scRNA-seq) data (GSE24757). An AI-based drug screen (DrugReflector) and molecular docking nominated therapeutic candidates. Finally, PPID expression was validated in an independent clinical cohort using q-RT-PCR. We identified a six-gene KN-associated signature that demonstrated excellent diagnostic performance. PPID can be considered upregulated hub gene. Single-cell analysis confirmed predominant PPID expression in NK cells and linked its function to epigenetic modification and inflammatory signaling. Drug screening nominated BRD-K90382497 as a potential PPID-targeting compound. This study unveils a novel KN-associated molecular axis in KD pathogenesis, with PPID as an NK cell-centric hub. This axis provides a promising diagnostic biomarker and identifies a potential therapeutic target, bridging a novel metabolic modification to NK cell dysfunction in KD.

Introduction:
Kawasaki disease (KD) is a systemic vasculitis of childhood driven by aberrant immune activation. Natural killer (NK) cell dysregulation plays a critical role, but its upstream molecular mechanisms remain unclear. Isonicotinylation (Kinic), a novel lysine acylation acting as a metabolic sensor, represents an unexplored regulatory layer in KD.

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