SiO2 dust induces the transformation of lung fibroblasts to myofibroblasts by activating the S1P-RhoA-YAP signaling pathway.

Silicosis, a prevalent and severe form of pneumoconiosis, is characterized by silicotic nodule formation and extensive pulmonary fibrosis. Caused by prolonged inhalation of free silica (SiO₂) dust, its pathogenesis involves complex regulatory mechanisms that remain unclear. Using a co-culture model of THP-1 macrophages and HFL-1 cells exposed to SiO₂, we investigated the role of the S1P-RhoA-YAP pathway in fibroblast-to-myofibroblast transformation. Intervention with fingolimod or si-RhoA was employed. Results showed that SiO₂ exposure significantly reduced HFL-1 cell viability, induced morphological changes (fibroblastic shape, loss of nucleoli), and enhanced migration. Protein levels of fibrotic markers (α-SMA, Col-III), inflammatory cytokines (TGF-β1, IL-1β), S1P, and RhoA increased, while p-LATS1 decreased. Notably, YAP underwent nuclear translocation with elevated nuclear YAP/TEAD expression. These effects were reversed by fingolimod or si-RhoA intervention, restoring cell viability and morphology, reducing migration and fibrotic markers, increasing p-LATS1, and inhibiting YAP nuclear translocation. Our findings demonstrate that SiO₂-activated macrophages promote fibroblast transformation via the S1P-RhoA-YAP pathway, a process effectively blocked by inhibiting S1P-S1PR1 binding or RhoA silencing. This study provides insights into silicosis pathogenesis and offers experimental evidence for its prevention and control.