Neurovascular-Immune Biomarkers in Ménière Disease: Insights From High-Throughput Proteomics

Background: M & eacute;ni & egrave;re disease (MD) is a chronic inner ear disorder characterized by recurrent vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. Diagnosis is clinical, and no validated peripheral biomarkers are available. Although endolymphatic hydrops is a hallmark, its poor correlation with symptom severity suggests broader systemic mechanisms.Methods: We performed large-scale serum proteomic profiling using the Olink Explore HT platform, quantifying 5400 proteins in patients with definite MD and matched controls. After quality control, 1037 proteins were analyzed through differential expression, protein-protein interaction mapping, and systems biology approaches.Results: MD exhibited a structured systemic proteomic signature characterized by 3 functionally integrated protein families in the upregulated proteome: (1) neuroendocrine and fluid-regulatory mediators (NPPB, POMC, CCK, NPY) converging on pathways controlling fluid homeostasis and HPA axis signaling; (2) morphogenetic and tissue-remodeling proteins (BMP6, SOST, FRZB, RSPO/SFRP) supporting extracellular matrix plasticity; and (3) cellular stress-adaptation proteins (FARSA, WARS1, BAG3) involved in translational control and proteostasis. The downregulated proteome revealed coordinated suppression of epithelial maintenance factors (EGF, SBDS) and neutrophil immune effectors (MMP8, OLFM4, RNASE3) alongside attenuation of NF-kappa B signaling, indicating dysregulation of tissue repair and immune surveillance rather than hyperinflammation. Tissue enrichment highlighted autonomic and vascular compartments in the upregulated signature, while neutrophil and hematopoietic lineages dominated the downregulated profile, supporting a neurovascular-immune interface.Conclusions: MD emerges as a systemic neurovascular-immune disorder characterized by activation of compensatory neuroendocrine-vascular-proteostatic pathways coupled with dysregulation of tissue repair and immune effector mechanisms, rather than solely a hydropic condition. The identified serum proteomic signature provides a candidate biomarker framework for diagnostic support, patient stratification, and future longitudinal validation.