Fibroblast MrgprX2/B2 signaling drives hypertrophic scar fibrosis

  • Cell Rep. 2026 Jun 25;45(7):117616. doi: 10.1016/j.celrep.2026.117616.
Heng Xu  1 ,  Meiying Sheng  2 ,  Yuxin Jia  3 ,  Yi Luo  2 ,  Liyan Wu  4 ,  Luxian Zhou  5 ,  Zihan Wang  4 ,  Jiawei Sun  6 ,  Tianyi Shen  4 ,  Liqin Zhou  4 ,  Ting Wang  4 ,  Yan Liu  7 ,  Jing Feng  8 ,  Yixin Zhang  9
Affiliations
  • 1. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. Electronic address: [email protected].
  • 2. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 3. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; Department of Burn and Plastic Surgery, Beijing Children's Hospital, Capital Medical University, Beijing 100000, China.
  • 4. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai 201203, China.
  • 5. Research Center, Shanghai Archgene Biotechnology Co., Ltd, Shanghai 200011, China.
  • 6. Genekinder Medicaltech (Shanghai) Co., Ltd, Shanghai 200011, China.
  • 7. Department of Burn and Plastic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 8. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100000, China. Electronic address: [email protected].
  • 9. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. Electronic address: [email protected].
PMID: 42360879 DOI: 10.1016/j.celrep.2026.117616
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.

Keywords
CP: cell biology; CP: immunology; MrgprB2; MrgprX2; fibroblast; fibrosis; hypertrophic scar; skin.
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