Second-degree IIB burns cause dermal damage and vascular necrosis that can delay the healing process. Betel leaves (Piper betle L.) contain secondary metabolites with potential to support tissue regeneration. This study aimed to analyze the effects of ethanol extract betel leaf gel on VEGF and TGF-β levels and burn wound area in male Wistar rats (Rattus norvegicus). A true experimental post-test only control group design was employed, involving Wistar rats divided into five groups for 14 days: Negative Control, Positive Control (Silver Sulfadiazine 1%), 15% Gel (P1), 20% Gel (P2), and 25% Gel (P3). Wound area was measured using ImageJ, VEGF and TGF-β levels were analyzed using ELISA, and ligand-protein interactions were predicted through molecular docking. The results showed a significant difference in wound area changes among groups (Welch ANOVA, p=0.036). TGF-β levels increased significantly in a dose-dependent pattern (One-Way ANOVA, p=0.000), with the highest level in P3 (788.00 ± 117.01 pg/mL) compared with the Negative Control (276.22 ± 88.31 pg/mL). VEGF levels did not differ significantly (p=0.260), although P3 showed an 84.4% increase and was comparable to the Positive Control. Molecular docking confirmed dillapiole affinity for VEGFR1 (-6.1 kcal/mol) and the TGF-β receptor (-6.3 kcal/mol). Ethanol extract betel leaf gel demonstrated effects on burn wound healing, particularly through increased TGF-β levels and improved wound area.
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