The emerging role of PDE4 inhibitors for the treatment of pulmonary fibrosis.

INTRODUCTION: Nerandomilast, a phosphodiesterase-4B (PDE4B) preferential inhibitor, was approved in 2025 for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). PDE4 enzymes play a central role in regulating intracellular cyclic adenosine monophosphate (cAMP) and are highly expressed in the lung. Through modulation of cAMP, PDE4 inhibition exerts pleiotropic effects on transforming growth factor-β (TGF-β)-dependent and independent signaling pathways, influencing numerous inflammatory and profibrotic processes involved in aberrant wound healing and fibrogenesis. These effects extend across immune cells, macrophages, alveolar epithelial cells, fibroblasts, and the pulmonary vasculature. AREAS COVERED: This review discusses the molecular mechanisms by which the PDE4/cAMP axis regulates pulmonary fibrosis and summarizes preclinical and clinical evidence supporting the development of nerandomilast. EXPERT OPINION: The pivotal FIBRONEER-IPF and FIBRONEER-ILD trials demonstrated significant reductions in the rate of FVC decline in patients with IPF and PPF, including those receiving background nintedanib therapy, establishing PDE4B inhibition as a new therapeutic strategy for pulmonary fibrosis. Beyond its demonstrated efficacy, nerandomilast represents a major therapeutic advance because of its favorable tolerability compared with earlier PDE4 inhibitors. As clinical experience with nerandomilast expands, real world data will be essential to better define its efficacy, tolerability, safety, and optimal clinical use.