Abstract

Hypertrophic scarring (HTS) represents a common clinical challenge characterized by excessive fibroblast activation and tissue fibrosis. However, the upstream signals driving pathological fibroblast proliferation remain poorly understood. Here, we identify the G protein-coupled receptor MrgprX2 (human)/MrgprB2 (mouse), traditionally restricted to mast cells, as an inducible pro-fibrotic receptor in dermal fibroblasts during HTS progression. MrgprX2 is markedly upregulated in dermal fibroblasts from HTS, and pharmacological inhibition of MrgprX2 significantly reduces fibrosis in humanized skin organoid models. In mouse studies, the endogenous peptide LL37 emerged as an MrgprX2/B2 activator in fibroblasts, triggering calcium influx, transforming growth factor β1 (TGF-β1) secretion, and proliferation. Genetic ablation of MrgprB2 in fibroblasts significantly reduced fibrosis in vivo , establishing the LL37-MrgprX2/B2-TGF-β1 axis as a key mediator of fibroblast activation and fibrotic remodeling. Together, our findings position MrgprX2/B2 as a critical molecular link between tissue injury-associated signals and fibrotic pathology, offering a promising therapeutic target for fibroblast-driven fibrosis in HTS.