Mechanistic insights into Hippo-YAP pathway activation for enhanced DFU healing

With the increasing prevalence of diabetes, diabetic foot ulcers (DFUs) have become a global health challenge, significantly impacting patients' quality of life and placing a substantial burden on healthcare systems. Among various immune cell subsets, M2-polarized macrophages play a pivotal role in tissue repair and inflammation resolution. This study uses single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing to comprehensively investigate the role of the TFAP2A-LIFR-Hippo-YAP signaling axis in regulating macrophage M2 polarization and its critical function in DFU wound healing. Through scRNA-seq analysis, we identified nine major immune cell subsets in DFU samples, with macrophages emerging as key regulatory cells. In vitro experiments further confirmed that TFAP2A promotes macrophage M2 polarization (evidenced by increased expression of the M2 marker ARG1) and ameliorates endothelial dysfunction by enhancing tube formation, improving migration capacity, and upregulating relevant proteins such as VCAM-1. Moreover, TFAP2A serves as a central regulatory gene for macrophage function in DFU by upregulating LIFR expression and activating the Hippo-YAP signaling pathway, thereby inducing M2 polarization and mitigating endothelial dysfunction. Mouse model experiments further demonstrated that the TFAP2A-LIFR-Hippo-YAP signaling axis accelerates DFU wound healing through the induction of macrophage M2 polarization. This study unveils a novel immunoregulatory role of TFAP2A in DFU and provides a promising therapeutic target for the treatment of chronic diabetic wounds.NEW & NOTEWORTHY This study provides unprecedented insights into diabetic foot ulcer healing by demonstrating the novel immunoregulatory role of the TFAP2A-LIFR-Hippo-YAP signaling axis. Leveraging single-cell and bulk transcriptomics, we identify TFAP2A as a crucial regulator of macrophage M2 polarization, essential for wound healing and angiogenesis. These findings offer valuable mechanistic understanding and present TFAP2A as a promising therapeutic target for improving outcomes in chronic diabetic wounds.