GALNT6-mediated O-glycosylation suppresses NLRP3 inflammasome activation to alleviate atopic dermatitis

Atopic dermatitis (AD) is characterized by chronic cutaneous inflammation, but the endogenous mechanisms that restrain excessive inflammatory activation remain unclear. This study investigated the role of GALNT6 in AD and its potential association with NLRP3 inflammasome regulation.

Public transcriptomic datasets were integrated to identify differentially expressed genes in AD. GALNT6 expression was validated in clinical skin samples, an MC903/OVA-induced AD-like mouse model, and an inflammatory keratinocyte model. GALNT6 was knocked down using siRNA. Inflammatory responses, NLRP3 inflammasome activation, protein association, and NLRP3 O-glycosylation were evaluated using histological, molecular, immunofluorescence, co-immunoprecipitation, and VVA lectin pull-down assays. The effects of topical retinol treatment were also assessed in AD-like mice.

GALNT6 was consistently upregulated in AD lesions and experimental AD models. GALNT6 knockdown aggravated skin lesions, epidermal thickening, inflammatory cytokine expression, ASC speck formation, and Caspase-1/GSDMD/IL-1β signaling. GALNT6 co-precipitated with NLRP3, while GALNT6 deficiency reduced the VVA-enriched NLRP3 signal, suggesting an association between GALNT6 and NLRP3 O-glycosylation. Retinol treatment increased GALNT6 expression and alleviated AD-like inflammation in a dose-dependent manner.

GALNT6 may function as a compensatory protective regulator of cutaneous inflammation by modulating NLRP3 O-glycosylation and inflammasome activation. These findings identify the GALNT6-NLRP3 pathway as a potential target for further mechanistic and therapeutic investigation in AD.