Nerandomilast, a PDE4B inhibitor, alleviates silica‐induced lung inflammation and fibrosis by inhibition of NLRP3 inflammasome and TGF‐β/Smad signalling

Background and Purpose Silicosis is a major cause of occupational disease‐related morbidity and mortality worldwide, yet effective pharmacological treatments remain limited. Nerandomilast, a novel inhibitor of phosphodiesterase‐4B (PDE4B), has demonstrated anti‐fibrotic potential in idiopathic pulmonary fibrosis (IPF); however, its efficacy and mechanisms in silicosis have not been investigated. Experimental Approach The therapeutic effects (and their underlying mechanisms) of PDE4B inhibition was evaluated in in models of silicosis, both in vivo (male C57BL/6N mice) and in vitro (THP‐1 macrophages and MRC‐5 cells). Single‐cell RNA sequencing, using lung tissue, was first performed to identify PDE4B as a key regulatory target in the pathogenesis of silicosis. Based on this finding, the therapeutic effects and underlying mechanisms of PDE4B inhibition were assessed using nerandomilast. Pulmonary function tests, inflammatory marker analyses and fibrosis evaluations were conducted to determine treatment efficacy. In addition, bulk RNA sequencing and transcriptomic analyses were performed to explore the molecular pathways modulated by nerandomilast. Key Results PDE4B inhibition effectively prevented and attenuated silica‐induced lung inflammation in the mouse model by suppressing both canonical and non‐canonical NLRP3 inflammasome pathways in lung macrophages. Furthermore, PDE4B inhibition down‐regulated TGF‐β/Smad signalling in lung fibroblasts of silicosis, leading to a significant reduction in fibrosis‐related gene expression. Conclusions and Implications These findings suggest that nerandomilast, a PDE4B inhibitor, may be a promising treatment for silicosis, which currently lacks effective therapies.