A Systemic Pathophysiological View of Sensitive Skin Revealed by Proteomics: Beyond Barrier and Inflammation.

BACKGROUND: Sensitive skin (SS) is a common dermatological condition characterized by enhanced reactivity to environmental, chemical, and cosmetic stimuli, often accompanied by impaired barrier function and discomfort sensation such as burning or itching. Despite its high prevalence, the molecular mechanism underlying SS remains poorly understood. OBJECTIVES: This study aimed to perform a comprehensive proteomics analysis to characterize molecular alterations in SS compared with nonsensitive skin (NS), thereby uncovering key pathways involved in barrier dysfunction, oxidative stress, and neuroinflammatory responses. METHOD: Thirty subjects with SS and 30 with NS were recruited. Stratum corneum samples were collected via tape stripping and analyzed using four-dimensional data-independent acquisition (DIA) proteomics. RESULTS: Proteomic profiling revealed distinct molecular signatures between SS and NS. SS exhibited enrichment of pathways related to cytoskeletal remodeling, cell-cell adhesion, and tight junction organization, consistent with impaired but dynamically compensatory barrier regulation. Enhanced oxidative phosphorylation and fatty acid β-oxidation indicated increased metabolic activity, while elevated glutathione-related enzyme functions reflected altered redox balance and oxidative stress. Additionally, upregulation of MAPK signaling and neurotrophin-associated pathways suggested active neuro-inflammatory crosstalk, potentially contributing to heightened cutaneous sensitivity and inflammatory susceptibility. Additional alterations were observed in other cellular processes, reflecting the complex molecular landscape of SS. CONCLUSION: These findings provide new insights into the molecular basis of SS, highlighting the interplay between barrier dysfunction, oxidative stress, and neuronal activation. The identified proteins and pathways may serve as potential biomarkers for SS assessment and as targets for the development of cosmetic products or therapeutic strategies aimed at restoring skin homeostasis.