Pantethine Restores Epidermal Homeostasis and Modulates Vesicle‐Associated Proteins in Psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by disrupted epidermal homeostasis driven by interconnected immuno-inflammatory, metabolic, and redox signalling networks. Vesicle-associated intercellular communication has emerged as an important contributor to inflammatory amplification and tissue remodelling within the epidermal microenvironment. Pantethine, a stable vitamin B5 derivative with lipid-modulatory and anti-inflammatory properties, has been implicated in regulation of cellular stress responses and membrane-associated signalling pathways, suggesting potential therapeutic relevance in psoriasis. Here, we investigated the effects of pantethine using a full-thickness 3D human psoriatic skin model following keratinocyte safety assessment. Integrated histopathological, immunohistochemical, quantitative RT-PCR, and proteomic analyses were employed to interrogate inflammatory, oxidative, proliferative, apoptotic, differentiation-associated and vesicle-related responses. Pantethine significantly reduced epidermal thickening and normalized multiple psoriasis-associated molecular signatures. Proteomic profiling revealed coordinated modulation of vesicle-associated, cytoskeletal and extracellular matrix-related proteins, accompanied by reduced expression of exosome-associated markers CD63 and CD9. Pantethine suppressed pro-inflammatory signalling involving IL-1β, TNF-α, IL-17, S100 family members, and hyperproliferative keratin-associated pathways while reducing caspase-3-associated apoptotic activity. Concurrently, pantethine enhanced antioxidative and immunoregulatory responses through activation of Nrf-2 and TGF-β, restored differentiation and barrier-related markers including filaggrin, caspase-14, and involucrin, and reduced hypoxia- and tissue-remodelling-associated mediators including HIF-1α, VEGF, COL6A3, and COL1A2. Network-based proteomic analyses further identified computationally inferred associations with SLIT/ROBO-related pathways, although these associations require further functional validation. Collectively, these findings support pantethine as a promising candidate that modulates vesicle-associated proteins together with inflammatory and tissue-remodelling responses involved in epidermal homeostasis.