Protective Effects of Jiawei Baihu Tang in Kawasaki Disease: Omics Analysis and Mechanistic Exploration.

Kawasaki disease (KD) is classified as a "WenBing" syndrome in traditional Chinese medicine (TCM), characterized by systemic inflammation and vasculitis. Jiawei Baihu Tang (JWBHT) is an optimized herbal formulation derived from the classical Baihu Tang (BHT), a renowned ancient TCM prescription traditionally used to treat WenBing syndromes by clearing heat, reducing fever, and promoting body fluid production. However, the precise pharmacological mechanisms underlying JWBHT's intervention effects remain largely unexplored. We aimed to assess the protective effects of JWBHT on coronary artery inflammation in mice with KD and explore the underlying mechanisms, with a focus on the lipocalin-2/matrix metalloproteinase 9 (LCN2/MMP9) axis in vascular remodeling. Histopathological analysis, multiplex immunofluorescence, data-independent acquisition (DIA) proteomics, and non-targeted metabolomics were employed to comprehensively measure the effects of JWBHT on coronary artery injury. The experiments were conducted using a Candida albicans water-soluble fraction (CAWS)-induced murine model of KD vasculitis. Multi-omics integration also revealed the role of JWBHT in regulating extracellular matrix (ECM)-receptor interaction and enhancing α-linolenic acid metabolism. JWBHT significantly alleviated coronary arteritis by reducing inflammatory cell infiltration, preserving ECM integrity, and alleviating fibrosis. Multi-omics analysis indicated that JWBHT regulated ECM-receptor interaction and restored lipid metabolism, particularly α-linolenic acid metabolism, which was closely linked to ECM stabilization. Mechanistically, JWBHT suppressed the LCN2/MMP9 axis, a critical mediator of vascular remodeling. Validation based on the clinical dataset revealed elevated levels of LCN2/MMP9 in patients with acute KD, which were normalized after treatment. For the first time, this study unveiled the multi-target mode of action of JWBHT in KD through the crosstalk between ECM and lipid metabolism, and LCN2 was identified as a potential novel intervention target. Our findings suggest that JWBHT is a promising traditional Chinese medicine for preventing the cardiovascular complications of KD.