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Objective: To investigate the effects of the sphingosine-1-phosphate receptor-2 (S1PR2) inhibitor JTE-013 on pulmonary fibrosis in silicosis mice and its underlying molecular mechanisms. Methods: In October 2024, 40 SPF male C57BL/6J mice were randomly divided into control group, JTE-013 control group, silicosis model group, and JTE-013 treatment group. A silicosis model was established by non-exposure intratracheal instillation of SiO(2) suspension. One week after model was establishment, mice in the JTE-013 treatment group were intraperitoneally injected with JTE-013 (10 mg/kg, twice a week for a total of 6 times), while mice in other groups were intraperitoneally injected with the same volume of normal saline. After 28 d of modeling, the lung coefficients of mice in each group were detected. The lung tissues were stained with HE, Masson, and Sirius Red to assess pathological damage and collagen deposition. The content of hydroxyproline (HYP) was determined. The expressions of S1PR2, epithelial-mesenchymal transition (EMT) marker proteins [E-cadherin (E-cad), Vimentin, α-smooth muscle actin (α-SMA) ], and Ras homolog family member A/Rho-related coiled helix kinase 1 (RhoA/ROCK1) pathway proteins were detected by protein immunoblotting method. Human alveolar epithelial A549 cells were cultured in vitro. The cells were divided into normal control group (cultured in complete medium for 26 h), JTE-013 control group (cultured in medium prepared to 1 μmol/L JTE-013 solution for 26 h), SiO(2) treatment group (cultured for 2 h with normal medium, then treated with 50 μg/ml SiO(2) suspension for 24 h), and SiO(2)+JTE-013 treatment group (pre-treated with 1 μmol/L JTE-013 for 2 h, then added 50 μg/ml SiO(2) suspension for 24 h). After group intervention, the expression levels of S1PR2, EMT-related proteins, RhoA and ROCK1 in the cells were detected. For the normally distributed measurement data, one-way ANOVA analysis of variance was used for inter-group comparison, and LSD-t test was used for pairwise comparison. Results: Compared with the control group, the mice in the silicosis model group had a significant decrease in body weight, and their lung coefficient and HYP content were significantly increased (P<0.05), silicotic nodules formed in the lungs, accompanied by collagen deposition. And the expression levels of SIPR2 protein, EMT-related proteins Vimentin, α-SMA, and the RhoA and ROCK1 proteins in signaling pathway were significantly increased, while the expression level of the epithelial marker E-cad was significantly decreased (P<0.05). Compared with the silicosis model group, the mice in the JTE-013 treatment group had a significantly increase in body weight, the lung coefficient and HYP content were significantly decreased (P<0.05), the pulmonary fibrosis was significantly reduced. And the expression levels of SIPR2 protein, EMT-related proteins Vimentin, α-SMA, and the RhoA and ROCK1 proteins in the signaling pathway were significantly decreased, while the expression level of the epithelial marker E-cad was significantly increased (P<0.05). In the in vitro experiments, compared with the normal control group, the expression levels of EMT-related proteins Vimentin, α-SMA and the proteins RhoA and ROCK1 in the signaling pathway in the SiO(2) treatment group were significantly increased, while the expression level of the epithelial marker E-cad was significantly decreased (P<0.05). Compared with the SiO(2) group, the expression levels of EMT-related proteins Vimentin, α-SMA, and the proteins RhoA and ROCK1 in the signaling pathway in the SiO(2)+JTE-013 treatment group were significantly decreased, while the expression level of the epithelial marker E-cad was significantly increased (P<0.05) . Conclusion: JTE-013 can alleviate the pulmonary fibrosis in silicosis mice, which may be related to the inhibition of the EMT process through the RhoA/ROCK1 signaling pathway.