MY-1 promotes angiogenesis in the ischemic hindlimbs by regulating the stability of CDC42 via PSMD14.

Critical limb ischemia (CLI) is a refractory peripheral artery disease characterized by tissue ischemia, presenting significant therapeutic challenges. Current surgical revascularization treatments are limited by indications, complications, and other constraints, making the identification of novel therapeutic strategies an important objective for CLI management. In this study, we designed and synthesized a novel short peptide, named MY-1, and developed a GelMA/MY-1 hydrogel sustained-release system for local application in a mouse hindlimb ischemia model. This system significantly promoted blood flow reperfusion and muscle tissue repair in the ischemic region. In vitro experiments revealed that MY-1 promoted the formation of filopodia in endothelial cells, accelerating cell migration and confirming the critical role of CDC42 in this process. Importantly, we found that MY-1 regulates the stability of CDC42, driving endothelial cell dynamics. Building on this, we identified PSMD14 as a novel upstream target influencing CDC42 stability. Silencing PSMD14 impaired filopodia formation, migration ability, and CDC42 stability in endothelial cells, and MY-1 could not reverse these effects. This indicates the potential of MY-1 in regulating deubiquitinase activity in angiogenesis.