Antifibrotic Strategies Targeting Phosphodiesterase-4 in Idiopathic Pulmonary Fibrosis: Molecular Mechanisms and Clinical Translation.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterised by irreversible fibrosis of the lung parenchyma and a steady decline in respiratory function. Its pathogenesis remains incompletely understood, and despite advances in diagnosis and disease management, therapeutic options remain limited and largely palliative. Emerging evidence suggests that phosphodiesterase-4 (PDE4) inhibitors may represent a novel therapeutic approach in IPF through modulation of cyclic adenosine monophosphate-dependent signalling pathways. Preclinical and clinical studies indicate that PDE4 inhibition can attenuate key pathological processes implicated in IPF, including macrophage-driven inflammatory responses, dysregulated epithelial repair, and fibroblast proliferation and differentiation. Through these mechanisms, PDE4 inhibitors demonstrate combined anti-inflammatory and antifibrotic effects in experimental models of lung fibrosis. Among this class, the PDE4B-selective inhibitor nerandomilast has shown encouraging signals of efficacy in clinical trials of IPF, supporting continued investigation of subtype-selective targeting strategies. Other PDE4 inhibitors, including roflumilast, rolipram, and structurally novel derivatives such as 2-arylbenzofurans, have also demonstrated antifibrotic activity, predominantly in preclinical studies. This review synthesises current evidence on the role of PDE4 signalling in IPF pathogenesis and critically evaluates the pharmacological rationale, therapeutic potential, and translational challenges of PDE4 inhibitors in the treatment of IPF. Future perspectives, including subtype-selective inhibition and optimised drug delivery strategies, are discussed as potential avenues to improve efficacy and tolerability in this patient population.