MC1R determines healing outcomes in acute and chronic cutaneous wounds.

Chronic wounds (CWs) represent a major clinical challenge, characterized by persistent inflammation and failed repair. While proresolving pathways are known to regulate inflammatory responses, their potential dysfunction in CWs remains unexplored. Here, we identify dysregulation of the pro-opiomelanocortin-melanocortin 1 receptor (POMC-MC1R) axis as a common feature across pressure ulcers, venous ulcers, and diabetic ulcers. Using MC1Re/e mice lacking functional MC1R, we demonstrate impaired wound healing marked by delayed reepithelialization and increased neutrophil extracellular traps-pathological features observed in human CWs. To investigate MC1R's therapeutic potential, we developed a new murine CW model that replicates human pathology, presenting as nonhealing, exudate-rich ulcers. Topical application of the MC1R-selective agonist BMS-470539 restored healing by reducing exudate production, stimulating vascularization, and enabling reepithelialization. The critical role of MC1R was further evidenced by MC1Re/e mice, which developed more severe ulcers with excessive exudate and NETosis. In acute wound studies, we found that topical MC1R agonist enhanced wound bed perfusion and lymphatic drainage through increased angiogenesis and lymphangiogenesis and reduced scarring by modulating fibroblast phenotype. Together, these findings establish the MC1R/POMC axis as a fundamental regulator of skin repair and identify promising therapeutic strategies to drive healing.