The role of PTP1B in cardiometabolic disorders and endothelial dysfunction.

Abstract

Cardiovascular diseases (CVD) are a global health concern that accounts for a large share of annual mortality. Endothelial dysfunction is the main underlying factor that eventually leads to cardiovascular events. Recent studies have underscored the critical function of Protein Tyrosine Phosphatase 1B (PTP1B) in the onset of endothelial dysfunction, chiefly through its involvement in metabolic diseases such as diabetes, obesity, and leptin resistance. PTP1B attenuates insulin and leptin signalling by dephosphorylating their respective receptors at key tyrosine residues, resulting in resistance-both of which are significant mechanisms underpinning the development of endothelial dysfunction. PTP1B also contributes to the disruption of the endoplasmic reticulum, causing endoplasmic reticulum stress, another molecular driver of endothelial dysfunction. Efforts to inhibit PTP1B activity hold the promise of advancing the prevention and management of CVD and metabolic disorders, as these conditions share common risk factors and underlying cellular mechanisms. Numerous small molecules have been reported as PTP1B inhibitors; however, their progression to advanced clinical trials has been hindered by major challenges such as low selectivity and undesirable side effects. This review provides an in-depth analysis of PTP1B's involvement in metabolic diseases and its interaction with CVD and examines the strategies and challenges related to inhibiting this enzyme.