Introduction: Inhaled treprostinil (iTre) has recently emerged as a therapeutic option for severe pulmonary hypertension associated with interstitial lung disease (PH-ILD), combining pulmonary vasodilatory, antiproliferative, and potential anti-fibrotic effects, while minimizing systemic exposure and ventilation-perfusion mismatch.

Areas covered: This review provides a comprehensive overview of iTre in PH-ILD, including its mechanisms of action, clinical efficacy, safety profile, and emerging applications in fibrotic ILD.

Expert opinion: The phase 3 INCREASE study demonstrated improvements in exercise capacity, reduction in N-terminal pro-brain natriuretic peptide levels, and attenuation of clinical worsening events with iTre. Post-hoc analyses suggest potential benefits on lung function and ILD exacerbations, particularly in idiopathic pulmonary fibrosis, while efficacy appears less pronounced in combined pulmonary fibrosis and emphysema or in patients with milder pulmonary vascular disease. iTre is generally well tolerated, with airway-related adverse events most common, and systemic effects limited. Emerging long-acting and dry-powder inhaled formulations aim to improve adherence, reduce dosing frequency, and extend the therapeutic potential to fibrotic ILD without PH. iTre has thus emerged as the first targeted therapy for PH-ILD, with unique pharmacological and biological properties. Remaining challenges include optimal patient selection, confirmation of long-term benefits, and integration with antifibrotic or other pulmonary vasodilator therapies.