Pedunculoside promotes oral ulcer healing in mice by upregulating STAT3 and Smad3

Oral ulcers are common, painful lesions with complex etiologies including trauma, immune dysregulation, and infections. Despite available treatments, effective and rapid healing strategies remain limited. This study explored the therapeutic potential of Pedunculoside (PE), a bioactive compound derived from the traditional Chinese medicinal plant Ilex rotunda Thunb., in accelerating oral ulcer healing and examined the underlying molecular mechanisms.

Using a mouse model of oral ulceration, the researchers found that PE significantly improved healing outcomes. Mice treated with PE exhibited a cure rate of 85.7% within 7 days, compared to lower recovery rates in untreated controls. Histological analysis suggested enhanced epithelial repair and reduced inflammatory response in the PE-treated group.

To elucidate the cellular mechanisms, primary oral mucosal fibroblasts were isolated and used to establish an in vitro model. Treatment with PE led to a significant increase in fibroblast proliferation and collagen secretion, both critical for tissue regeneration. At the molecular level, PE upregulated the gene transcription of Smad3, Col1a1, and Col3a1, all of which are associated with extracellular matrix (ECM) remodeling and collagen biosynthesis. PE did not affect fibroblast migration, suggesting its healing effect is primarily due to enhanced proliferation and matrix production.

One of the key findings was that PE could antagonize the inhibitory effect of WP1066, a known STAT3 pathway inhibitor, thereby restoring STAT3 activation. This highlights a dual mechanism involving STAT3 and Smad3 signaling pathways, both of which are critical regulators of inflammation, cell growth, and tissue repair. The activation of these pathways by PE underlines its multifaceted role in wound healing.

PE has previously been shown to have anti-inflammatory, lipid-lowering, and anticancer properties. Its application in this study extends its pharmacological scope to mucosal regeneration, aligning with traditional uses of Ilex extracts in treating oral and gastrointestinal disorders. Given its natural origin, favorable safety profile, and biological efficacy, PE represents a promising candidate for the development of novel topical or systemic therapies for oral ulcerations.

This research not only supports the clinical relevance of PE in oral wound healing but also provides insights into its mechanism of action, paving the way for future studies and potential clinical applications in oral medicine and regenerative therapies.