JunB orchestrates macrophage-fibroblast crosstalk in silica nanoparticle-induced pulmonary fibrosis

Silica nanoparticles (SiNPs) exposure represents a significant environmental and occupational hazard leading to pulmonary fibrosis; however, the underlying molecular mechanisms remain incompletely understood. This study aimed to elucidate the role of JunB signaling in SiNPs-induced pulmonary fibrosis and evaluate its therapeutic potential. A comprehensive experimental approach combining in vitro macrophage-fibroblast co-culture systems and in vivo mouse models was employed, utilizing both pharmacological inhibition and genetic silencing strategies to investigate the function of JunB. RNA sequencing analysis was performed to identify differential gene expression patterns and potential regulatory pathways. SiNPs exposure induced macrophage pyroptosis, subsequently promoting fibroblast transdifferentiation through JunB/AP-1 pathway activation. Notably, genetic silencing of JunB significantly attenuated the expression of transdifferentiation markers in fibroblasts exposed to pyroptotic macrophage-conditioned medium. Furthermore, pharmacological inhibition of JunB using T-5224 effectively suppressed fibroblast transdifferentiation in vitro. Importantly, intraperitoneal administration of T-5224 substantially ameliorated pulmonary fibrosis in SiNPs-exposed mice, as evidenced by reduced collagen deposition and decreased expression of fibrotic markers. In conclusion, this study establishes JunB as a critical mediator of SiNPs-induced pulmonary fibrosis and demonstrates the therapeutic potential of JunB inhibition, which provides new insights for developing targeted treatments for lung fibrosis.