System‐Local Axes and Metabolic Reprogramming From Health to Response in House Dust Mite‐Specific Subcutaneous Immunotherapy for Allergic Rhinitis

ABSTRACT Allergic rhinitis (AR) features mucosal inflammation and systemic immune activation; the coordination of local and circulating metabolism during disease and immunotherapy is unclear. We performed untargeted LC‐MS metabolomics on paired plasma and nasal secretion samples from 28 house dust mite (HDM)‐induced AR patients before and after 6 months of subcutaneous immunotherapy (SCIT), together with 19 healthy controls. Over 1800 annotated metabolites revealed compartmentalized metabolic reprogramming in AR. Nasal secretions displayed disrupted lipid, steroid, and redox metabolism linked to epithelial injury and local inflammation, while plasma had altered nucleotide and NAD + metabolism reflecting systemic type 2 inflammatory stress. After clinically effective SCIT, metabolic profiles shifted toward healthy status, with nasal metabolites showing stronger treatment‑associated changes. Two exploratory candidate axes were observed: a plasma nucleotide/NAD + axis potentially reflecting systemic immunometabolic burden, and a nasal lipid‐steroid‐redox axis possibly linked to mucosal remission, yielding candidate features that may support future longitudinal surveillance. Combined local and systemic metabolomics reveals asynchronous yet coordinated immunometabolic remodeling throughout AR onset and SCIT intervention, providing candidate features for future development of noninvasive strategies to assess disease activity and therapeutic response.