Serum Proteomic Profiling Uncovers Dysregulated Keratinisation and Immune‐Related Pathways in Hidradenitis Suppurativa

ABSTRACT Hidradenitis suppurativa (HS) is an autoinflammatory keratinisation disease affecting the pilosebaceous unit and hallmarked by a complex and multifactorial pathogenesis. Although genomic and transcriptomic investigations have substantially advanced our understanding of key mechanisms underlying HS pathogenesis, proteomic studies remain limited, despite the significant potential of serum proteomics to identify molecular signatures reflecting both cutaneous and systemic inflammatory activity. This exploratory study presents a serum proteomic analysis of patients with moderate‐to‐severe HS, identifying 306 differentially abundant proteins out of 3153 profiled (FDR q < 0.10). Sensitivity analysis at q < 0.05 (194 proteins) confirmed a robust inflammatory signature, while the FDR q < 0.10 threshold was necessary to preserve markers of epidermal homeostasis, which are inherently diluted in systemic circulation. Enrichment analyses revealed dysregulated pathways related to keratinisation, epidermal differentiation and extracellular matrix (ECM) remodelling, indicating impaired skin barrier function. Concurrent higher abundance of immune‐related pathways, including defence response to bacterium, complement activation and neutrophil degranulation, suggest systemic inflammation potentially linked to microbial dysbiosis. These findings suggest the dual role of epithelial dysfunction and autoinflammation in HS pathogenesis. Integration of proteomic data with genomic and transcriptomic findings underscores the value of multi‐omics approaches in guiding targeted therapeutic development.