Promising signalling pathways for the treatment of pulmonary arterial hypertension

Improved understanding of the complex and interconnected mechanisms driving pulmonary arterial hypertension (PAH) has expanded therapeutic development beyond the traditional vasodilator pathways. This review summarizes recently established and emerging signalling pathways that may influence the next generation of targeted PAH therapies.

The transforming growth factor-β (TGF-β) superfamily has emerged as a fourth major therapeutic pathway. Therapies that target this pathway, such as the activin signalling inhibitor sotatercept, have demonstrated significant clinical and hemodynamic benefits in large randomized clinical trials. Additional promising strategies focus on receptor tyrosine kinases - particularly platelet-derived growth factor receptor signalling - as well as hypoxia-related and metabolic reprogramming pathways. Growing evidence also supports the role of immune dysregulation, hormonal and neurohormonal signalling, and epigenetic, genetic, and cell-cycle abnormalities in the development of PAH.

The therapeutic landscape in PAH is shifting toward mechanism-based therapies with the potential to modify disease progression. Continued translational research and upcoming clinical trials will be essential to define appropriate patient selection, optimize therapeutic strategies, and determine the short- and long-term benefit of these therapies on clinical and survival outcomes.