Histological Evaluation of Mentha spicata Essential Oil in a Rat Excisional Wound Model with Network-Based Mechanistic Insights

Background/Objectives: Wound healing is a complex biological process involving inflammatory, proliferative, and remodeling phases. Plant-derived essential oils are increasingly investigated as topical therapeutic agents, although their biological effects are strongly influenced by composition and formulation. The present study evaluated the effects of topical Mentha spicata essential oil on cutaneous wound healing in a rat excisional wound model and explored potential molecular mechanisms using a network-based bioinformatic approach. Methods: Twenty-one male Wistar rats were randomly assigned to three groups and treated twice daily for 14 days with a formulation containing 5% Mentha spicata essential oil diluted in olive oil, olive oil alone, or no treatment. Wound healing was assessed through macroscopic monitoring and histological scoring. The chemical composition of the essential oil was characterized using gas chromatography–mass spectrometry analysis. Predicted molecular targets of the major monoterpenes were analyzed through protein interaction networks and pathway enrichment analysis. Results: Macroscopic wound closure progressed in all groups by day 14. Histological analysis revealed that the olive oil group showed more advanced collagen deposition, re-epithelialization, and granulation tissue maturation, whereas the Mentha spicata group displayed a more pronounced inflammatory and proliferative histological pattern. Network-based analysis highlighted signaling pathways related to receptor-mediated cellular responses as potential molecular mechanisms associated with early inflammatory and proliferative processes. Conclusions: These findings suggest that the biological effects of Mentha spicata essential oil in wound repair may be phase-dependent and influenced by concentration and formulation. The results support further studies aimed at optimizing dose and delivery strategies for essential oil–based wound therapies.