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 Silica or PBS group. The Silica 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 When contrasted with individuals in good health, a differential expression analysis of mRNA in patients with pneumoconiosis identified a total of 584 mRNAs with significant expression differences. Among these, the expression of 242 mRNA was observed to be markedly elevated, while that of 342 mRNA was found to be considerably diminished. 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 Silica mice, the alveolar structures were compromised, characterized by the presence of collagen fiber accumulation and the formation of fibrous masses. In contrast, the PBS mice maintained a normal pulmonary architecture. GIMAP8 expression was up-regulated whereas SEC14L5 expression was down-regulated in lung tissues in the Silica mice, and mice in the Silica group had poorer lung function. Conclusions The onset and progression of pulmonary fibrosis may be significantly influenced by GIMAP8 and SEC14L5 expression in patients with pneumoconiosis and in silicosis animal models. This association could serve as a foundational molecular insight, paving the way for the development of preventative and therapeutic strategies against these conditions.