Breakthroughs in our molecular understanding of therapeutic targets for pulmonary hypertension

INTRODUCTION: Pulmonary hypertension (PH) is characterized by progressive pulmonary vascular remodeling, rising right-ventricular afterload, and eventual maladaptation, which is a major determinant of prognosis. While established therapies mainly target vasoconstrictive pathways, recent development has shifted toward disease-modifying strategies that address remodeling, inflammation, and metabolic dysfunction in PH patients. AREAS COVERED: This Special Report summarizes selected breakthrough therapeutic targets in PH, focusing on mechanisms supported by strong causal rationale and evaluated in at least Phase II clinical testing. Covered pathways include bone morphogenetic proteins/activin signaling rebalancing, growth factor and kinase inhibition, zinc transport targeting, inflammatory and immune-directed approaches, and metabolic modulation. We emphasize translational relevance, current clinical status, and key challenges limiting broader implementation of these approaches. EXPERT OPINION: The next advance in PH treatment will depend not only on identifying effective targets but also on improving precision in their deployment. Three barriers are especially important: responder heterogeneity, incomplete benefit-risk stratification, and uncertainty about target engagement in vivo. Therefore, biomarker-guided enrichment, integrated safety profiling, and practical pharmacodynamic readouts should become central elements of trial design. In parallel, expansion of the therapeutic toolbox, including stress-sensing, adrenergic, senescence, and hypoxia-related pathways, may increase the likelihood of matching individual patients to effective disease-modifying therapy.