PCSK6 is a novel regulator of venous smooth muscle cell function in arteriovenous fistula remodeling.

The arteriovenous fistula (AVF), the preferred vascular access for hemodialysis, is limited by neointimal hyperplasia. Although proprotein convertase subtilisin/kexin type 6 (PCSK6) is involved in vascular smooth muscle cell (VSMC) activation, its role in AVF stenosis is unclear. PCSK6 expression was significantly upregulated in VSMCs of human and murine stenotic AVFs and correlated with the severity of neointimal hyperplasia. In vitro, PCSK6 overexpression promoted VSMC proliferation, migration, contractility, and extracellular matrix (ECM) synthesis, whereas PCSK6 knockdown suppressed these processes. Mechanistically, PCSK6 directly interacted with STAT1 and enhanced its phosphorylation, with STAT1 inhibition reversing PCSK6-driven effects. In vivo, smooth muscle cell-specific PCSK6 knockout in mice on a high-glucose diet attenuated neointimal formation, improved AVF lumen diameter and blood flow, and enhanced vasodilation. In conclusion, PCSK6 drives AVF neointimal hyperplasia by binding and activating STAT1 to promote VSMC phenotypic switching and ECM remodeling, identifying the PCSK6/STAT1 axis as a novel mechanism and potential therapeutic target for preventing AVF failure.