Objective To investigate the improvement effect and mechanism of polydeoxyribonucleotide (PDRN) on lung injury in rats with acute pulmonary embolism (APE). Methods Fifty rats were randomly divided into sham group, model group, cyclic GMP-AMP synthase (cGAS) inhibitor (RU.521) group, PDRN group, PDRN+interferon gene stimulator (STING) agonist (2′3′-cGAMP) group, with 10 rats in each group. Except for the sham group, the other four groups were replicated with APE model. Before modeling, RU.521 group, PDRN group, PDRN+2′3′-cGAMP group were intraperitoneally injected with 5 mg/kg RU.521, 8 mg/kg PDRN, 8 mg/kg PDRN and 1 mg/kg 2′3′-cGAMP, respectively, and the sham operation group and model group were intraperitoneally injected with an equal amount of normal saline. 4 hours after surgery, the pulmonary artery pressure (mPAP), right ventricular pressure (RVP), oxygen partial pressure (PaO2) and carbon dioxide partial pressure (PaCO2) of the rats in each group were detected, the wet weight and dry weight of the lung tissue of the rats in each group were weighed and the lung wet-to-dry weight ratio was calculated, hematoxylin-eosin (HE) staining was used to observe the pathological changes of the lung tissue of the rats in each group. The superoxide dismutase (SOD) and myeloperoxidase (MPO) activities and malondialdehyde (MDA) content of the lung tissue of the rats in each group were determined by kits. The real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) combined with western blot was used to determine the expression of cGAS and STING in the lung tissue of the rats in each group. Results Compared with the model group, the mPAP and RVP levels of rats in the RU.521 group and the PDRN group were significantly decreased (P＜0.05), the PaO2 level was significantly increased (P＜0.05), the lung wet-to-dry weight ratio was significantly decreased (P＜0.05), the lung tissue pathological phenomena such as alveolar expansion or collapse, inflammatory cell infiltration were significantly improved, the SOD activity of lung tissue was significantly increased, the MPO activity and MDA content were significantly decreased (P＜0.05), and the relative expression levels of cGAS, STING mRNA and protein were significantly downregulated (P＜0.05). Compared with the PDRN group, the mPAP and RVP levels of rats in the PDRN+2′3′-cGAMP group were significantly increased (P＜0.05), the PaO2 level was significantly decreased (P＜0.05), the lung wet-to-dry weight ratio was significantly increased (P＜0.05), the lung tissue showed alveolar rupture, exudate and a large number of inflammatory cell infiltration, the SOD activity of the lung tissue was significantly decreased, the MPO activity and MDA content were significantly increased (P＜0.05), and the relative expression of cGAS, STING mRNA and protein were significantly upregulated (P＜0.05). Conclusion PDRN improves lung injury in APE rats by inhibiting the activation of the cGAS/STING signaling pathway