Catecholaminergic neurons boost fibroblast osteogenic activity in keloid

Keloids represent a paradigm of fibroproliferative disorders marked by abnormal extracellular matrix deposition, yet the neuronal-stromal interactions driving fibroblast dysregulation remain poorly understood. Through single-cell RNA sequencing of human keloid specimens, we identify RUNX family transcription factor 2 (RUNX2)+ osteogenic fibroblasts exhibiting ectopic integrin-binding sialoprotein (IBSP) deposition, consistent with a hybrid fibro-osseous reprogramming. Keloid fibroblasts display catecholamine response signatures, correlating with excessive tyrosine hydroxylase-positive adrenergic innervation in keloid stroma. Crucially, β1-adrenergic receptor (ADRB1) activation by epinephrine/norepinephrine induces IBSP production exclusively in keloid-derived fibroblasts via canonical cAMP–PKA–CREB signaling. Through detailed mechanistic analysis, we demonstrate that CREB-activated Translin (TSN) facilitates nuclear-to-cytoplasmic IBSP mRNA transport, enabling efficient translation in RUNX2+ fibroblasts. Therapeutic interventions targeting catecholamine biosynthesis or adrenergic innervation, and pharmacological inhibition or genetic ablation of ADRB1 effectively prevent keloid-like pathology in a rodent model. Our study provides the demonstration of neuronal-adrenergic signaling driving fibrotic/osteogenic matrix overproduction through TSN-mediated RNA trafficking, revealing therapeutic targets for keloid management. RUNX2+ keloid fibroblasts highly expressing ADRB1 produce bone matrix proteins in response to neurotransmitters from catecholaminergic nerves. Blocking this neuro-stromal interaction prevents fibro-osseous reprogramming and keloid progression.