Cathepsin D as a central regulator of extracellular matrix remodeling in wound healing and chronic tissue pathologies

Wound healing is a dynamic and multifactorial process involving coordinated interactions among extracellular matrix (ECM) components, growth factors, proteolytic enzymes, and immune and stromal cells. An essential yet often underappreciated aspect of this process is restoration of the epithelial permeability barrier, which prevents fluid loss and microbial invasion following injury. Disruption of this coordination contributes to chronic, non-healing wounds such as diabetic ulcers and venous leg ulcers, which remain major clinical challenges. Recent advances identify cathepsins, particularly cathepsin D, as key proteases that extend beyond lysosomal degradation to regulate critical events in tissue repair. Cathepsin D modulates keratinocyte proliferation, fibroblast invasion, angiogenesis, and ECM remodeling, and supports re-epithelialization through processing of structural proteins such as transglutaminase 1. Emerging evidence indicates that cathepsin D indirectly influences junctional remodeling, including tight and adherens junction dynamics, thereby facilitating permeability barrier reformation during wound closure. Its activity is regulated by oxidative stress, advanced glycation end products, inflammatory mediators, and iron metabolism - factors highly relevant to chronic wound microenvironments. Beyond proteolysis, cathepsin D shapes fibroblast and macrophage phenotypes and processes vascular endothelial growth factor (VEGF), integrating metabolic and signaling pathways essential for tissue regeneration. Collectively, these findings position cathepsin D as a mechanistic regulator and promising therapeutic target in wound biology. This review synthesizes mechanistic insights linking cathepsin D-mediated proteolysis to epithelial junction reorganization and permeability barrier recovery, and highlights emerging therapeutic strategies for improving chronic wound healing.