Topical Timolol Improves Hypertrophic Scar Remodeling Associated With MMP13 Upregulation

Hypertrophic scarring arises from dysregulated wound healing, which is characterized by excessive extracellular matrix deposition and abnormal collagen remodeling. This study investigated the therapeutic effects and molecular mechanisms of topical timolol, a nonselective β ‐adrenergic receptor blocker, using a rabbit ear model of hypertrophic scars. Treatment with timolol significantly reduced scar hypertrophy and erythema, decreased scar thickness, and promoted organized collagen fiber alignment. Histological and biochemical analyses revealed that timolol reduced the proportion of Type I collagen while relatively preserving Type III collagen in scar tissue. qPCR analysis showed that COL1A1 and COL3A1 mRNA levels were not significantly altered, whereas MMP13 expression was significantly increased, suggesting that timolol primarily affects extracellular matrix remodeling rather than directly suppressing collagen gene transcription. Transcriptomic profiling and immunohistochemistry further supported the involvement of ERK1/2 activation and MMP13 upregulation in timolol‐treated scars. In contrast, betaxolol, a β 1 ‐selective blocker, showed weaker effects on scar thickness and collagen remodeling than timolol. Collectively, the data indicate that topical timolol improves hypertrophic scars in association with ERK1/2 activation, increased MMP13 expression, and enhanced extracellular matrix remodeling. These results provide preliminary mechanistic insights into the antifibrotic effects of nonselective β ‐adrenergic receptor blockade and support further evaluation of timolol in hypertrophic scar remodeling.