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

ABSTRACT

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.