Objective To explore the expression of disc large homology-associated protein 5 (DLGAP5) in the hypoxic pulmonary hypertension(HPH). Methods This study first used bioinformatics analysis to explore the expression of DLGAP5 in normal control group and HPH group. Then, lung tissue samples from 9 patients undergoing lung transplantation with HPH and 4 controls were collected, and the expression level of DLGAP5 in different lung tissues was detected by Western blot (WB). Rat models of Sugen5416 combined with chronic hypoxia(SuHx) was constructed to detect the mean pulmonary artery pressure(mPAP). The pulmonary vascular remodeling and the expression of DLGAP5 in HPH were detected by hematoxylin-eosin (HE) staining, immunohistochemistry (IHC) staining and immunofluorescence (IF) staining. Finally, differential gene enrichment analysis was used to explore the downstream signaling pathway of DLGAP5 regulating HPH. Results DLGAP5 was significantly upregulated in the lung tissue of HPH patients (P<0.05). The mPAP of SuHx-induced HPH model rats was significantly increased (P<0.05). The results of HE staining and IHC staining showed that the pulmonary artery media was thickened and obvious vascular remodeling occurred in the HPH model rats. The results of IF staining showed that compared with the control group, the expression of DLGAP5 in pulmonary artery media smooth muscle in HPH rats was increased (P<0.05), and it was mainly distributed in the cytoplasm. Finally, differential gene enrichment analysis, including GO and GSEA analysis, suggested that DLGAP5 may regulate HPH by influencing the cell cycle, especially the G2/M phase (P<0.05). Conclusions DLGAP5 may be a potential new target for HPH, bringing new ideas for the diagnosis and treatment of pulmonary hypertension.