miR-301a-5p regulated IKKβ/NF-κB axis and macrophage polarization to accelerate skin wound healing

Wound healing is a highly coordinated biological process encompassing four distinct yet interconnected stages. Notably, microRNA (miRNA) dysregulation is related to non-healing wounds, and miRNAs are considered promising therapeutic targets for wound healing. However, its function and underlying mechanism in wound healing remain incompletely understood. Here, we detected and characterized the miRNA expression patterns during wound healing. Interestingly, miR-301a-5p was significantly downregulated in the initial inflammatory stage and finally peaked in early proliferative phases, suggesting its potential role in modulating phase transition from inflammatory to proliferative phase. Moreover, miR-301a-5p not only promoted the proliferation and migration of macrophages, but also suppressed the excessive inflammatory response, as evidenced by both facilitating the expression of IL-10 and TGF-β and suppressing the pro-inflammatory factors expression. Mechanistically, miR-301a-5p directly targeted inhibitor of κB kinaseβ (IKKβ) and regulated its expression to modulate nuclear factor κB (NF-κB) pathway and macrophage polarization (M1 to M2). Importantly, miR-301a-5p overexpression significantly promoted the regeneration of full-thickness skin wound in mice by regulating NF-κB and macrophage polarization, thereby facilitating epidermal regeneration and collagen deposition. Together, our study found that miR-301a-5p as a novel regulator in the wound healing process transition, and provided potent pro-healing agents for wound healing.