Endothelial system dysregulation underlies keloid development and therapeutic targeting.

Cutaneous keloids are pathological scars resulting from aberrant wound healing, characterized by infiltrative growth beyond the original wound margins and a failure to regress spontaneously. Although traditionally attributed to excessive extracellular matrix deposition and fibroblast proliferation, emerging evidence underscores the pivotal role of vascular dysregulation and endothelial dysfunction in keloid pathogenesis. This review systematically examines the endothelial cell system-comprising vascular endothelial cells (VECs) and lymphatic endothelial cells (LECs)-within the keloid microenvironment, focusing on how hypoxia, chronic inflammation, mechanical forces, sex hormones, the renin-angiotensin system, and neuropeptides converge to drive structural and functional endothelial abnormalities. Special emphasis is placed on endothelial-to-mesenchymal transition (EndMT) as a critical pathway linking vascular pathology to fibrotic progression. Additionally, we comprehensively summarize current and emerging therapeutic strategies targeting the endothelium, including anti-angiogenic agents, HIF-1α inhibition, EndMT blockade, mechanical offloading, hormonal modulation, renin-angiotensin system (RAS) inhibition, and laser therapy. By providing an integrated overview of the endothelial mechanisms underlying keloid formation and persistence, this review aims to illuminate novel targets for therapeutic intervention and to inform the development of more effective clinical management strategies.