Combined Therapy Using Nerandomilast and Nintedanib Enhances Treatment of Silica-Induced Silicosis in Mice

Silicosis, a chronic occupational lung disease from silica dust inhalation, features progressive pulmonary fibrosis. While antifibrotics Nerandomilast and Nintedanib show individual efficacy, monotherapy often inadequately addresses complex disease needs. This study evaluated their combined therapeutic potential and mechanisms in a silica-exposed mouse silicosis model. Results demonstrated that combination therapy surpassed monotherapy in alleviating pulmonary fibrosis and inflammation. The enhanced efficacy stemmed from synergistic/complementary suppression of key pathological processes: pulmonary fibroblast proliferation, activation, migration, and extracellular matrix (ECM) deposition; pulmonary epithelial cell epithelial-mesenchymal transition (EMT); and pro-inflammatory cytokine release by M1 macrophages. Mechanistically, the combination synergistically/complementarily inhibited pivotal fibrotic pathways (TGF-β1-Smad/non-Smad) and inflammatory pathways (NF-κB and JAK2/STAT1), explaining its superior anti-fibrotic and anti-inflammatory effects. These findings highlight the potential of the combination therapy of Nerandomilast and Nintedanib as a promising therapeutic strategy for the treatment of silicosis and other fibrotic lung diseases. Future studies should further explore the detailed molecular mechanisms and long-term therapeutic effects of this combination therapy in both preclinical and clinical settings to fully realize its potential in the management of fibrotic diseases.