YAP1 Activation Rescues Nagashima-type Palmoplantar Keratosis Pathological Features in Skin Organoid Disease Models

ABSTRACT: YAP1 activation rescues NPPK pathological features Abstract Nagashima-type palmoplantar keratosis (NPPK), a recessive genetic skin disorder, is characterized by the presence of keratosis on the palmar and plantar regions, resulting from SERPINB7 mutation. However, the detail pathogenesis of NPPK remains elusive. This study revealed that SERPINB7 does not interact with proteolytic enzymes directly. Instead, SERPINB7 mutants disrupt keratinocyte proteolysis by down-regulating the expression of KLKs, and MMPs in NPPK epidermis. Mechanistically, SERPINB7 mutants inhibit keratinocyte glycolytic metabolism by reducing HK1 kinase activity, which subsequently impedes the activation, and nuclear translocation of transcription factor YAP1. This cascade ultimately leads to decreased expression of proteolytic enzymes within the KLKs, and MMPs families in keratinocytes. Furthermore, we successfully established a skin organoid disease model harboring the SERPINB7 c.796C>T mutation, faithfully recapitulating the clinical, and molecular features of NPPK lesions. Notably, treatment of NPPK skin organoid models with YAP1 agonists significantly improved the pathological changes of the disease. In summary, our findings offer novel insights into the molecular mechanisms underlying NPPK pathogenesis and identify YAP1 as a promising therapeutic target for this disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285879 | GEO | 2025/01/10

REPOSITORIES: GEO