Gasdermin D Promotes Skin Wound Healing by Regulating Inflammatory Resolution and Macrophage M2 Polarization

Gasdermin D (GSDMD), the canonical executor of pyroptosis, plays an important role in regulating inflammation. However, its role in skin wound healing remains unclear. Timely macrophage phenotypic transition is important for tissue repair, yet whether GSDMD influences skin wound healing by modulating macrophage polarization has not been fully explored. Here, we established a full-thickness excisional skin wound model in Gsdmd knockout mice and performed complementary macrophage-based in vitro assays to examine the effects of GSDMD deficiency on skin wound healing, inflammation, and macrophage polarization. GSDMD deficiency significantly delayed wound closure, reduced collagen deposition, disrupted extracellular matrix organization and remodeling, and delayed the resolution of wound inflammation. It was also associated with impaired macrophage polarization toward the M2 phenotype and reduced levels of reparative mediators in wound tissues. Consistent with these findings, macrophage and fibroblast coculture assays showed that GSDMD deficiency in macrophages was associated with reduced fibroblast migration and lower levels of reparative factors in the coculture system. Collectively, these findings suggest that GSDMD may be involved in coordinating inflammatory resolution and macrophage phenotypic transition during wound healing and play an important role in maintaining a local immune microenvironment that supports tissue repair. They also provide an experimental basis for further investigating the role of GSDMD in skin wound healing and its potential value for therapeutic intervention.