【Abstract】Objective Utilizing transcriptomic sequencing, this study aimed to monitor the expression alterations of GIMAP8 and SEC14L5 throughout the progression of pulmonary fibrosis, thereby providing insights into the underlying mechanisms of its pathogenesis and evolution. Methods C57BL/6 male mice were assigned in a randomized manner to either the experimental or control cohorts. The model group underwent non-exposed endotracheal intubation on days 0 and 14 with 50 μL 100 mg/mL silica suspension, while the control group received 50 μL phosphate-buffered saline solution. On day 28, lung function was detected and the mice were sacrificed, and lung morphology, fibrosis, and mRNA levels were observed. Results The pneumoconiosis group was found to have a total of 2,988 mRNAs compared with the control group, of which 626 mRNAs showed large expression differences, including 242 up-regulated and 384 down-regulated genes. The enrichment analysis indicated that the primarily affected mRNAs with altered expression were associated with pathways such as p53, nuclear factor-κB, tumor necrosis factor, AMP-activated protein kinase, and other signaling pathways. In the model mice, the alveolar structures were compromised, characterized by the presence of collagen fiber accumulation and the formation of fibrous masses. In contrast, the control mice maintained a normal pulmonary architecture. GIMAP8 expression was up-regulated whereas SEC14L5 expression was down-regulated in lung tissues in the model mice, and mice in the model group had poorer lung function. Conclusions The onset and progression of pulmonary fibrosis may be significantly influenced by GIMAP8 and SEC14L5 expression in the blood in patients with pneumoconiosis and in silicosis animal models.