Bioactive Peptide HX ‐ 12C Ameliorates Oral Submucous Fibrosis via Inhibition of TGF ‐β/Smad‐Driven Myofibroblast Activation: A Potential Therapeutic Strategy

OBJECTIVES: To investigate the anti-fibrotic effects and mechanism of action of the bioactive peptide HX-12C in oral submucous fibrosis. MATERIALS AND METHODS: Primary human buccal mucosal fibroblasts were treated with arecoline to induce a myofibroblast phenotype. The effects of HX-12C on cell proliferation, migration and fibrotic markers were assessed. Molecular docking and immunofluorescence were used to examine HX-12C binding to transforming growth factor-beta receptor I, validated by the inhibitor SB-431542. In vivo efficacy was evaluated in a bleomycin-induced rat model of oral submucous fibrosis. RESULTS: HX-12C promoted fibroblast proliferation and migration but suppressed arecoline-induced myofibroblast activation, downregulating alpha-smooth muscle actin, fibronectin and collagens I/III. Mechanistically, HX-12C bound to transforming growth factor-beta receptor I, inhibited SMAD2/3 phosphorylation and downstream pro-fibrotic gene expression, effects attenuated by SB-431542. In vivo, HX-12C improved mouth opening and reduced collagen deposition. CONCLUSIONS: HX-12C exerts potent anti-fibrotic effects by directly targeting transforming growth factor-beta receptor I and inhibiting the canonical transforming growth factor-beta/Smad signalling pathway. Our findings identify HX-12C as a promising therapeutic candidate for oral submucous fibrosis and provide a rationale for developing peptide-based therapies for transforming growth factor-beta-driven fibrotic diseases.