Insights into Silica-Induced Lung Fibrosis: Fibrotic Gene Signatures, Pathways, and Therapeutic Opportunities.

Silica exposure is a significant environmental hazard linked to lung inflammation and fibrosis. This study utilized in-silico analysis of publicly available transcriptomic datasets (GSE250537 and GSE142446) from silica-exposed Fischer 344 rats to investigate molecular pathways and potential therapeutic targets. Rats were exposed to crystalline silica via inhalation, and transcriptomic data from lung and blood samples were analyzed at four post-exposure intervals (1-day, 3-month, 6-month, and 9-month). Gene set enrichment analysis (GSEA) revealed the activation of fibro-inflammatory and aging pathways in lung tissue, including TGF-beta, NLRP3, and TNF-α signaling, with limited effects in blood transcriptomes. Differential expression analysis identified 12 key fibrotic markers consistently upregulated in lung tissue, such as Cxcl6, Mmp12, and S100a9, which are involved in inflammation, tissue remodeling, and fibrosis. Temporal analysis indicated prolonged upregulation of fibrotic markers up to 9 months post-exposure. Protein-protein interaction networks highlighted clusters related to chemokine signaling, tissue remodeling, and matrix metalloproteinases. Using the open-TG gate database, 179 pharmacological agents were identified as potential treatments, with 37 targeting five or more fibrotic genes. Notable candidates include NSAIDs, captopril, and simvastatin, offering promising therapeutic avenues to mitigate silica-induced lung pathology. In vivo validation in a silica-induced murine fibrosis model further demonstrated that simvastatin treatment significantly reduced the expression of key fibro-inflammatory genes and attenuated the increase in fibrotic markers in lung tissue. These findings provide insights into silica immunopathology and potential drug repurposing strategies; however, further studies are warranted to elucidate underlying mechanisms and evaluate therapeutic efficacy in clinical settings.