Effects of Nerandomilast on Alveolar Type 2 Cell Senescence and Fibrosis-Related PATS Accumulation in Pulmonary Fibrosis

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease. Nerandomilast, a preferential phosphodiesterase 4B (PDE4B) inhibitor, has shown promise in mitigating lung function decline with a more favourable safety profile compared to nonselective PDE4 inhibitors. Given the emerging evidence implicating alveolar type 2 (AT2) cell dysfunction and the pathological accumulation of pre-alveolar type-1 transitional cell state (PATS) in PF pathogenesis, this study investigates the effect of nerandomilast on cellular senescence and lung fibrosis with concomitant PATS accumulation. Methods: Mice received intratracheal bleomycin (BLM) on day 1, followed by oral administration of nerandomilast (12.5 mg/kg) twice daily from day 10–20. Antifibrotic effects were assessed on day 21 using hydroxyproline assay and Masson’s trichrome staining. Cellular senescence was evaluated via p21 and γH2AX staining. PATS marker expression dynamics were analysed on day 10 and 21. Additionally, primary human AT2 organoids were used to assess the effect on KRT17 induction, a marker of human basaloid cells corresponding to mouse PATS. Results: Nerandomilast significantly attenuated the BLM-induced lung fibrosis and reduced cellular senescence. Additionally, nerandomilast suppressed BLM-induced expression of CLDN4 and KRT8, indicating its role in mitigating pathogenic PATS accumulation. In human AT2 organoids, nerandomilast reduced fibrosis cocktail-induced KRT17 expression. Conclusion: Nerandomilast exerts significant antifibrotic effects by reducing the accumulation of senescent cells, represented by profibrotic PATS, and may prevent basaloid cell differentiation.