KDM5A, a H3K4me3 Demethylase, Regulates Skin Wound Healing by Promoting M2 Macrophage Polarization via Suppression of Socs1

Jixun Zhang^*Chao WangXinxin Dong

• The Second Hospital of Shandong University, Jinan, China

The inflammatory response represents a critical phase in wound healing, wherein a heterogeneous array of immune cells is recruited and activated to orchestrate tissue repair and regeneration. Among these, macrophages (Mφs) emerge as indispensable immune mediators, with their polarization states and secretory profiles of inflammatory factors exerting profound regulatory effects on wound repair. KDM5A, a pivotal histone demethylase, governs chromatin remodeling and transcriptional regulation. Recent studies have elucidated its capacity to epigenetically suppress the expression of Socs1, a key negative regulator of immune responses that modulates cytokine signaling pathways. However, the precise mechanistic contributions of KDM5A and Socs1 to cutaneous wound healing remain poorly characterized. Consequently, this study aims to delineate the functional role of KDM5A in wound repair, with particular emphasis on its regulatory crosstalk with Socs1 in macrophages. To elucidate the impact of KDM5A on wound healing, we first established a murine wound model, systematically evaluating wound closure kinetics, collagen deposition, healing scores, macrophage polarization dynamics, and inflammatory cytokine profiles. Subsequently, we employed an in vitro co-culture system of macrophages and fibroblasts subjected to KDM5A perturbation to assess how KDM5A-mediated macrophage polarization influences fibroblast proliferation, migration, and angiogenic capacity. Further mechanistic interrogation via chromatin immunoprecipitation (ChIP) assays revealed the epigenetic regulatory role of KDM5A on Socs1, thereby clarifying its functional implications for macrophage polarization and wound repair. Our findings demonstrate that KDM5A expression is significantly downregulated in wound-associated macrophages, exhibiting an inverse correlation with M2 polarization. Genetic ablation of KDM5A accelerated cutaneous wound closure in mice, concomitant with enhanced collagen deposition and improved healing scores. Mechanistically, KDM5A deficiency elevated H3K4me3 and H3K27ac histone modifications at the Socs1 locus, augmenting its transcriptional activation. The resultant upregulation of Socs1 not only promoted M2 macrophage polarization but also attenuated inflammatory cytokine secretion while stimulating fibroblast proliferation, migration, invasiveness, and angiogenesis—collectively fostering wound repair. In summary, this study elucidates the molecular axis through which KDM5A modulates Socs1 expression to drive M2 macrophage polarization, thereby facilitating wound healing. These insights establish a conceptual framework for the development of innovative therapeutic strategies, bearing substantial translational relevance in clinical wound management.