Objective: This study aimed to investigate the expression of fibroblast-derived Galectin-3 (LGALS3) in lung tissue of a silica (silicon dioxide, SiO?)-induced pulmonary fibrosis mouse model and its relationship with extracellular matrix (ECM) deposition, further elucidating the role of LGALS3 in the mechanism of silicosis fibrosis. Methods: A pulmonary fibrosis mouse model was established by silica exposure, and collagen deposition and structural changes in lung tissues were observed using Sirius Red staining and polarized light microscopy. Then, single-cell clustering analysis was performed to classify cells into 20 clusters, and differentially expressed genes upregulated in fibroblasts after 56 days of SiO? treatment were identified. Gene Ontology enrichment analysis using Metascape was conducted to identify genes associated with ECM binding. In vitro, human lung fibroblasts (HPF-a) and mouse lung fibroblasts (MLg) were stimulated with transforming growth factor-β1 (TGF-β1), and the expression levels of LGALS3 and its deposition on the ECM were detected by Western Blot and immunofluorescence staining. Results: Single-cell clustering analysis showed a significant increase in fibroblast numbers after 56 days of SiO? treatment, with the top ten upregulated genes identified as Ccl6, Lyz2, Ftl1, Spp1, Lgals3, Cxcl2, Fth1, Psap, S100a9, and Ctss. GO enrichment analysis indicated that these genes were closely associated with ECM binding, with Ctss, Lgals3, and Spp1 being the core related genes. Dot plots and violin plots demonstrated that the expression level of Lgals3 was significantly higher in the SiO? 56-day group compared to the control group. Sirius Red staining and polarized light microscopy revealed significantly increased collagen deposition and dense structure in the lung tissues of the SiO?-exposed group, exhibiting typical pathological features of pulmonary fibrosis. Western Blot results showed that LGALS3 expression in HPF-a cells exhibited a time-dependent increase after TGF-β1 stimulation, peaking at 12 hours (P < 0.05). Animal model validation confirmed that LGALS3 expression in lung tissues of the SiO?-exposed group was significantly higher than in the control group (P < 0.001), and immunofluorescence staining revealed enhanced co-localization signals of LGALS3 with the fibroblast marker Vimentin (P < 0.01). Furthermore, after seeding TGF-β1-stimulated MLg cells onto ECM, LGALS3 expression levels significantly increased (P < 0.05); even after cell removal, LGALS3 expression on the ECM remained higher than in the control group (P < 0.05). Conclusion: This study confirms that fibroblast-derived LGALS3 is significantly upregulated in lung tissues of a silica-induced pulmonary fibrosis mouse model and participates in ECM deposition. The expression of LGALS3 is regulated by TGF-β1 and shows persistent accumulation on the ECM. These findings reveal the critical role of LGALS3 in pulmonary fibrosis and provide new theoretical insights into the pathological mechanisms of silicosis and potential therapeutic targets.