Emerging significance of E3 ubiquitin ligases and Deubiquitinases in pulmonary hypertension.

Pulmonary hypertension (PH) is a progressive, life-threatening cardiovascular disorder. It features irreversible pulmonary vascular remodeling and causes right ventricular failure and mortality. The underlying pathogenesis of PH is incompletely elucidated. Ubiquitination is a reversible post-translational modification. It regulates protein degradation and membrane trafficking and contributes critically to PH development and progression. The ubiquitin-proteasome system (UPS), especially E3 ubiquitin ligases and Deubiquitinases, modulates the function of pulmonary artery endothelial cells and pulmonary artery smooth muscle cells in PH. These molecules exert distinct roles and regulatory mechanisms in PH-related signaling pathways. The pathways include bone morphogenetic protein, nuclear factor kappa B (NF-κB), hypoxia inducible factor-1α, P53, Hippo, and mitochondrial quality control. UPS-targeted small-molecule agents, proteasome inhibitors, and proteolysis-targeting chimeras have therapeutic potential for PH. They also face notable translational challenges. Ubiquitination provides new mechanistic insights into PH pathogenesis and identifies innovative avenues for targeted therapy.