miRNA regulatory networks as precision diagnostic and therapeutic targets in pulmonary arterial hypertension: from molecular cascades to clinical translation.

Pulmonary arterial hypertension (PAH) is a fatal disease with extremely poor prognosis, primarily driven by persistent pulmonary vascular remodeling. The disease often presents insidiously and progresses rapidly. Although current targeted therapies may slow disease progression, they fall far short of reversing pathological changes, underscoring the urgent need for novel therapeutic breakthroughs and precise diagnostic approaches. Within this context, microRNA (miRNA) regulatory networks - key nodes of epigenetic regulation - have emerged as a potential bridge between basic science and clinical translation. Increasing evidence has shown that specific miRNAs, by targeting signaling pathways such as PI3K/AKT and TGF-β/Smad, orchestrate complex multi-target molecular cascades that critically regulate pathological processes, including endothelial dysfunction, abnormal proliferation and phenotypic switching of smooth muscle cells, inflammatory activation, and metabolic remodeling. These mechanisms ultimately drive irreversible vascular remodeling. Aberrant expression patterns of miRNAs are not only closely associated with disease severity but also hold great promise as non-invasive biomarkers, facilitating early detection, subtype classification, and prognostic assessment of PAH. Importantly, miRNA-targeted nucleic acid therapeutics have demonstrated therapeutic potential in preclinical models, including reversal of vascular remodeling and improvement of hemodynamics, highlighting their potential in future precision medicine strategies. However, clinical translation faces multiple barriers, such as poor targeting efficiency of delivery systems, unpredictable off-target effects, significant inter-individual variability, and lack of standardized efficacy evaluation frameworks. Therefore, systematic breakthroughs are urgently needed. This review aims to comprehensively summarize the role of miRNA regulatory networks in the pathogenesis, diagnosis, and treatment of PAH, with a particular emphasis on their central position in shaping early-stage precision intervention strategies.