Abstract
The skin barrier is crucial for protecting against environmental challenges, preventing water loss, and regulating immune responses. This study aims to investigate the roles and mechanisms of SERPINB7 in skin barrier maintenance. We found that SERPINB7 deficiency disrupts tight junctions of keratinocytes in vitro, and specific knockout of Serpinb7 in keratinocytes impairs skin barrier function in vivo. SERPINB7 deficiency leads to reduced expression of O-GalNAc regulatory proteins and structural abnormalities in the Golgi apparatus, ultimately impairing protein O-GalNAc glycosylation. Legumain acts as a critical mediator in the maintenance of normal biological functions and O-GalNAc glycosylation regulated by SERPINB7. O-GalNAc inhibition exhibits biological effects analogous to those induced by SERPINB7 deficiency, leading to weakened tight junctions, reduced cell adhesion, and compromised skin barrier integrity in keratinocytes and mouse skin, respectively. Consequently, O-GalNAc deficiency exacerbates inflammatory skin diseases such as psoriasis and atopic dermatitis. Mechanistically, O-GalNAc deficiency primarily affects the glycosylation of calcium-related and cell adhesion-related proteins, disrupting calcium signaling and compromising cell adhesion, ultimately leading to skin barrier dysfunction. In summary, this study demonstrates that SERPINB7 maintains skin barrier through protein O-GalNAc glycosylation. These findings not only deepen our understanding of skin barrier biology but also provide new insights for developing therapeutic strategies for skin barrier-related diseases.