Nerandomilast alleviates myositis-associated interstitial lung disease by modulating the non-Smad signalling pathway and activating the cAMP–PKA–RhoA pathway

OBJECTIVES: Nerandomilast, a selective phosphodiesterase 4B (PDE4B) inhibitor, has been extensively investigated for the treatment of pulmonary fibrosis; however, its therapeutic potential and mechanisms of action in idiopathic inflammatory myopathies-associated interstitial lung disease (IIM-ILD) remain to be elucidated. METHODS: A myositis-associated ILD mouse model was treated with nerandomilast (BI 1015550), and lung pathology was assessed histologically. Human lung microvascular endothelial cells-5a were stimulated with neutrophil extracellular traps (NETs) to induce endothelial-mesenchymal transition (EndMT). Western blotting, immunofluorescence, qPCR and ELISA were employed to analyse pathways and cytokines. RESULTS: PDE4B was upregulated in the lungs of patients with IIM-ILD and in mice. Treatment with BI 1015550 significantly reduced lung inflammation and fibrosis scores, decreased inflammatory cytokines in bronchoalveolar lavage fluid and serum, alleviated muscle inflammation and lowered kinase activity without evident hepatorenal toxicity. Immunofluorescence and immunohistochemistry revealed diminished NET markers, reduced inflammatory cell infiltration (CD3, CD11b, F4/80), suppression of EndMT, downregulation of Ras homolog family member A (RhoA) and inhibition of key fibrotic pathways: phosphorylated phosphoinositide 3-kinase (P-PI3K), phosphorylated protein kinase B (P-AKT), phosphorylated p38 mitogen-activated protein kinase (P-P38), phosphorylated extracellular signal-regulated kinase (P-ERK), phosphorylated nuclear factor kappa-B (P-NF-κB). In vitro, BI 1015550 inhibited phorbol 12-myristate 13-acetate-induced neutrophil extracellular trap formation (NETosis) and EndMT. CONCLUSIONS: Nerandomilast alleviates IIM-ILD by inhibiting NET formation and suppressing EndMT in lung microvascular endothelial cells, potentially through non-Smad signalling pathway modulation and cAMP-PKA-RhoA pathway activation. These findings suggest that the specific inhibition of PDE4B is a potential therapeutic approach for IIM-ILD.