Misregulation of T-box transcription factors drives BNP–NPR1 signalling underlying chronic itch

Abstract Chronic itch poses a significant clinical burden, with activation of the brain natriuretic peptide (BNP) pathway as a hallmark, though its transcriptional control remains unclear. We identify T-box transcription factor 20 (TBX20) as upregulated in skin of atopic dermatitis patients, with increased expression in NPR1 + keratinocytes. ChIP peak calling, ChIP-qPCR and dual-luciferase assays show TBX20 activates the NPR1 promoter. In mice, keratinocyte-specific TBX20 knockout (TBX20 fl/fl ; K14-Cre) reduces scratching, IL-4 and Oncostatin M levels, basophil markers, and decreases cutaneous NPR1 expression. TBX20 is also expressed in a subset of NPR1 + sensory neurons, and neuron-specific deletion similarly alleviates itch, basophil infiltration, and barrier dysfunction. RNA-seq identifies lipocalin-2 as a downstream effector of the TBX20-NPR1 axis, and its deletion reduces itch. Conversely, AAV-mediated TBX20 rescue exacerbates symptoms. Neuregulin 1 suppresses TBX20, attenuates IL-13-driven NPR1 signalling, and reduces itch. These findings define a TBX20-NPR1 axis as a critical regulator of chronic itch and skin dysfunction.