Non‐Syndromic Hereditary Gingival Fibromatosis Driven by Chymase Deficiency Is Attenuated by Verteporfin‐Loaded Exosomes

Aim To identify novel non‐syndromic hereditary gingival fibromatosis (nsHGF)–associated pathogenic variants and discover therapeutic targets for innovative, minimally invasive therapies. Materials and Methods Whole‐genome sequencing was performed to identify the pathogenic variant in a family with nsHGF. Levels of fibrosis markers and the yes‐associated protein/transcriptional coactivator with PDZ‐binding motif (YAP/TAZ) in gingival fibroblasts were measured by qPCR, western blot and immunofluorescence. Conditioned medium from gingival fibroblasts was used to treat THP‐1‐derived macrophages. In vivo pro‐fibrotic behaviour of CHYMASE ‐silenced gingival fibroblasts and verteporfin‐loaded exosome efficacy were evaluated in NOD/SCID mice. Results We identified a novel CHYMASE ( CMA1 ) nonsense mutation (c.114C>A, p.Tyr38*) in the nsHGF family. This mutation caused chymase deficiency in the patient's gingival fibroblasts, directly leading to extracellular matrix (ECM) overproduction through YAP/TAZ activation. Moreover, CHYMASE ‐silenced gingival fibroblasts promoted interleukin‐6 (IL‐6) secretion by macrophages, thereby amplifying pro‐fibrotic responses in gingival fibroblasts. The YAP inhibitor verteporfin suppressed ECM overproduction in CHYMASE ‐silenced gingival fibroblasts. In vivo, topical administration of verteporfin‐loaded exosomes significantly attenuated chymase deficiency–induced fibrosis. Conclusion Our findings support the pathogenic role of the CHYMASE mutation in nsHGF, establish chymase deficiency and consequent YAP/TAZ activation as the underlying mechanism and propose verteporfin‐loaded exosomes as a promising therapeutic strategy for nsHGF‐associated gingival overgrowth.