Abstract: An experimental model of mouse pulmonary fibrosis induced by polyethylene terephthalate microplastics (PET-MPs) was established to explore the regulatory mechanism and role of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway regulated by transforming growth factor (TGF-β1) and epithelial-mesenchymal transition (EMT) in the process of PET-MPs-induced pulmonary fibrosis in mice. Four groups (8 mice per group) of BALB/c mice were exposed to PET-MPs through an oral and nasal exposure system, and were divided into a control group, a low-dose group of 500 mg/m³, a medium-dose group of 1 000 mg/m³, and a high-dose group of 2 000 mg/m³. The degree of pulmonary fibrosis in the mouse lung tissue was detected by hematoxylin-eosin (HE) and Masson staining. The expression levels of EMT-related markers such as α-smooth muscle actin (α-SMA) and type I collagen (Col-I) were determined by immunohistochemistry. The collagen deposition in the mouse lung tissue was evaluated by hydroxyproline content. The expression levels of Col-I, vimentin, α-SMA, and E-cadherin, which are markers of pulmonary fibrosis and EMT, were detected by Western Blot. The results of HE staining showed that the alveolar walls of the PET-MPs-exposed mice were thickened, with inflammatory cell infiltration and fibrous hyperplasia around the blood vessels. Masson staining showed that the collagen fiber content in the 1 000 and 2 000 mg/m³ PET-MPs-exposed mice was significantly increased. Immunohistochemistry showed that the deposition of α-SMA and Col-I proteins in the lung tissue of the 1 000 and 2 000 mg/m³ PET-MPs-exposed mice was more than that in the control group. Western Blot results showed that microplastic exposure significantly increased the expression levels of TGF-β1, α-SMA, and vimentin proteins (P <0.05), while the expression level of E-cadherin protein showed the opposite trend (P<0.05). At the same time, PET-MPs exposure had no significant effect on the expression of PI3K, AKT, and mTOR proteins, but significantly promoted their phosphorylation expression (P<0.05). The study indicates that the PI3K/AKT signaling pathway can activate EMT and excessive collagen deposition in the mouse pulmonary fibrosis model induced by PET-MPs. Research on the health hazards and regulatory mechanisms of microplastics is still in its early stages. The experimental results can provide evidence and data support for a comprehensive and in-depth exploration of the toxic effects of microplastics on organisms.