Protease-activated receptor 1 in diabetes and its chronic complications: signaling mechanisms and emerging therapeutic advances

Abstract

Diabetes mellitus (DM) is a systemic metabolic disorder characterized by chronic hyperglycemia, which can affect the kidneys, retina, peripheral nerves, and cardiovascular system, ultimately leading to multiple chronic complications. Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor activated through canonical cleavage, such as thrombin-mediated cleavage, and non-canonical cleavage, such as cleavage by activated protein C or matrix metalloproteinase-1. These activation modes initiate diverse downstream signaling pathways, including Gαq/PLC-β/PKC, Gα12/13/Rho, and β-arrestin-dependent signaling, and contribute to inflammation, fibrosis, angiogenesis, and apoptosis. This review summarizes the role of PAR1 in the pathogenesis of type 2 diabetes mellitus (T2DM), focusing on its effects on endothelial insulin resistance, adipose tissue inflammation, and brown adipose tissue dysfunction. We further discuss the pathogenic mechanisms of PAR1 in diabetic kidney disease, diabetic retinopathy, diabetic peripheral neuropathy, and diabetic cardiovascular disease. This review also outlines recent advances in PAR1-targeted therapies, including orthosteric antagonists such as vorapaxar, biased signaling modulators such as 3K3A-APC and parmodulins, and intracellular inhibitors such as PZ-128. Their therapeutic potential and current challenges in antithrombotic therapy and target-organ protection are also discussed, with the aim of informing more precise strategies for preventing and treating DM and its chronic complications.