Single-cell transcriptomics and spatial validation reveal dysfunction of keratinocytes and NK cells driving acne development.

Acne, the most prevalent inflammatory skin condition globally, lacks comprehensive understanding of its cellular and molecular mechanisms. This research integrates single-cell transcriptomics with spatial immunofluorescence to detail cellular composition and functional states in healthy skin, mild acne, and severe acne. Findings indicate that keratinocytes in mild acne secrete antimicrobial peptides and maintain barrier defense, but transition to abnormal differentiation and pathological keratinization in severe acne. Natural killer (NK) cells initially amplify inflammation and activate the immune response, but later become exhausted and apoptotic. This interaction creates a "dual immune-barrier imbalance," driving acne progression. Functional enrichment and pseudo-time analyses demonstrated a strong association between disease severity and TNF, and chemokine signaling pathways, as well as NK cell-mediated cytotoxicity and Wnt/p53-apoptosis pathways. These findings were corroborated by immunofluorescence validation. This study introduces an innovative pathological model that establishes theoretical foundations for early diagnosis and precision interventions, while also outlining future therapeutic strategies centered on "immune-barrier co-regulation." The findings provide essential insights into the pathogenesis of acne and open avenues for investigating novel intervention targets.