Circular RNAs regulate the progression of pulmonary hypertension through distinct roles and mechanisms

Pulmonary hypertension (PH) is a progressive, life-threatening vascular disorder driven by pulmonary vascular remodeling and right ventricular dysfunction. Circular RNAs have emerged as key regulators of PH pathogenesis. In this review, we critically evaluate circular RNA expression profiles in clinical and experimental PH samples and synthesize their functional roles into 5 core pathogenic modules. The first 4 modules focus on pulmonary vascular cells (smooth muscle cells and endothelial cells): (1) transforming growth factor-β/bone morphogenetic protein receptor type-2 and phosphoinositide 3-kinase signaling; (2) noncanonical cell death (ferroptosis, pyroptosis, and autophagy); (3) epitranscriptomic, chromatin, and posttranslational regulation; and (4) metabolic reprogramming. The fifth module addresses (5) right ventricular remodeling. We also discuss their biomarker potential, therapeutic strategies, delivery challenges, and limitations. Collectively, this modular framework reveals that numerous dysregulated circular RNAs converge on limited shared pathways, underscoring their diagnostic and therapeutic potential in PH. SIGNIFICANCE STATEMENT: This review offers insights into circular RNA functions across key pathological processes of pulmonary hypertension, with the overall goal of identifying shared molecular pathways and developing them as novel biomarkers and therapeutic targets for this intractable vascular disorder.