Targeting the Hippo pathway in pulmonary arterial hypertension: emerging pharmacological strategies

Pulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by pulmonary vascular remodeling and increased resistance, ultimately leading to right heart failure and high mortality. The Hippo signaling pathway has emerged as a key regulator of PAH development by influencing cell proliferation, apoptosis, and phenotypic changes in pulmonary artery smooth muscle cells (PASMCs), endothelial cells, and adventitial fibroblasts. Disruption of this pathway - especially involving its effectors YAP1 and TAZ - contributes to excessive cell growth, migration, endothelial-to-mesenchymal transition (EndMT), metabolic reprogramming, and inflammatory responses, collectively driving pathological vascular remodeling. Recent studies have highlighted the complex interaction between the Hippo pathway and signaling axes such as Notch, Transforming growth factor (TGF-β), Akt/mTOR, and integrin-linked kinase, emphasizing its extensive influence on disease progression. Emerging therapies targeting Hippo components and new small molecules, including natural products such as luteolin and resveratrol, offer promising options for reversing remodeling and treating PAH. However, the potential for Hippo-focused therapies is limited by the pathway's diverse roles and context-dependent effects. This narrative review covers recent progress in understanding Hippo signaling in PAH vascular remodeling, molecular mechanisms, and therapeutic prospects, laying a foundation for future targeted treatments.