DAPK1 Ablation Promotes Wound Healing by Keratinocyte Modulation

Abstract

Death-associated protein kinase 1 (DAPK1), a Ca²+/calmodulin-regulated serine/threonine kinase, plays a pivotal role in epidermal homeostasis, tissue repair, and cutaneous wound healing. However, its role in oral mucosal repair remains unclear. In this study, we established a global Dapk1 knockout mouse model to create 1.5-mm circular palatal wounds in mice aged 8 to 12 wk. Our results demonstrated that DAPK1 deficiency significantly accelerated oral wound closure. In vitro experiments further confirmed that DAPK1 modulates the proliferation and migration of human oral keratinocytes. Mechanistic investigations through transcriptome sequencing revealed activation of the Wnt signaling pathway in Dapk1 knockout mice following injury, characterized by pronounced upregulation of Wnt3 , Fosl1 , and Ctnnd2 , alongside downregulation of innate immune mediators, including Il7 , Ccl28 , Ccr2 , Ccl5 , and Cxcr4 . These findings suggest that loss of DAPK1 enhances epithelial proliferation and migration while attenuating local inflammation. Furthermore, we developed a novel microneedle patch for drug delivery, consisting of GelMA tips encapsulating the DAPK1 inhibitor (HS-38) and a hyaluronic acid substrate. This system facilitated efficient mucosal penetration and localized delivery. Application of the microneedle patch significantly improved wound healing in both normal and diabetic mouse models. Collectively, these findings uncover a previously unrecognized role of DAPK1 in oral mucosal repair and highlight its potential as a molecular target to accelerate wound healing.