Dynamic keratinocyte Piezo2 expression drives itch and nerve remodeling in atopic dermatitis

Keratinocytes actively contribute to somatosensory signaling in chronic skin diseases, yet the mechanotransduction mechanisms involved in atopic dermatitis (AD)-associated itch remain unclear. Here we identify keratinocyte-expressed mechanosensitive ion channel Piezo2 as a critical driver of chronic itch in AD. While Piezo1 was constitutively expressed and dispensable for chronic itch in the MC903-induced AD model, Piezo2 expression was markedly upregulated in keratinocytes of lesional AD skin. Keratinocyte-specific Piezo2 deletion attenuated spontaneous scratching and spontaneous C fiber activity, while having minimal impact on skin inflammation. Mechanistically, Piezo2 suppressed the neurorepulsive factor Semaphorin 3A (Sema3a), a key regulator of sensory nerve architecture. Loss of Piezo2 restored Sema3a expression in the epidermis, reduced nerve fiber branching, and dampened C fiber hyperexcitability. Furthermore, keratinocyte-specific ablation of Sema3a exacerbated AD-related itch and nerve fiber outgrowth. These findings establish a non-neuronal epithelial mechanism wherein keratinocyte Piezo2 modulates sensory nerve remodeling and pruritus in chronic skin inflammation, offering potential targets for therapeutic intervention.