Semaphorin 3C/Plexin D1 Interaction Regulates Collagen Metabolism in Keloid Fibroblasts via the Transforming Growth Factor-β1 Signaling Pathway

  • Am J Pathol. 2026 May;196(5):1169-1187. doi: 10.1016/j.ajpath.2026.02.007.
Yanqiu Tang  1 ,  Sihui Wang  1 ,  Yang Xu  1 ,  Yin Yang  1 ,  Xiaomei Cui  2 ,  Hui Hua  3 ,  Wenbo Bu  4 ,  Bingrong Zhou  5
Affiliations
  • 1. Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 2. Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.
  • 3. Department of Dermatology, Nantong Third People's Hospital Affiliated to Nantong University, Nantong, China.
  • 4. Department of Dermatologic Surgery, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China. Electronic address: [email protected].
  • 5. Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
PMID: 41833636 DOI: 10.1016/j.ajpath.2026.02.007
Abstract

This study aimed to identify novel signaling axes governing keloid pathogenesis by investigating the role of the semaphorin 3C (SEMA3C)/plexin D1 (PLXND1) pathway in fibrotic processes via transforming growth factor (TGF)-β1 signaling, using single-cell RNA Sequencing (scRNA-seq) and experimental validation. scRNA-seq analysis was performed on eight keloid and eight normal skin samples from four public data sets, using Seurat and CellChat to map intercellular communication networks. Primary keloid fibroblasts were treated with Recombinant SEMA3C, PLXND1-specific siRNA, or the TGF-β1 inhibitor SB431542. Transcriptome Sequencing, real-time quantitative PCR, Western blot analysis, and immunofluorescence were used to assess changes in Collagen I/III, fibronectin, and TGF-β1 expression. scRNA-seq revealed significantly enhanced intercellular communication in keloids, particularly among fibroblasts, with a 1.65-fold increase in interaction numbers and 17.79-fold stronger communication strength compared with normal skin. A critical ligand-receptor pair, SEMA3C (predominantly secreted by Schwann cells) and its receptor PLXND1 (overexpressed in keloid fibroblasts), was identified as the most prevalent in keloid samples. Experimental assays demonstrated that SEMA3C dose dependently up-regulated Collagen I/III, fibronectin, and TGF-β1 expression, whereas PLXND1 knockdown or TGF-β1 inhibition (via SB431542) attenuated these effects, confirming that SEMA3C/PLXND1 drives fibrosis through TGF-β1 signaling. This study is the first to demonstrate that the SEMA3C/PLXND1 axis drives keloid fibrosis by activating TGF-β1, promoting extracellular matrix deposition. Targeting this axis holds promise for keloid therapy.

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