OBJECTIVE: This study aimed to investigate the role and potential mechanism of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in chronic intermittent hypoxia (CIH)-induced mice and pulmonary arterial smooth muscle cells (PASMCs). METHODS: CIH mouse model was pre-injected with AAV-shPLOD2 by tail vein, and the pathological changes of lung was evaluated using hematoxylin-eosin (H&E) and α-SMA immunostaining. Enriched KEGG pathway analyses of PLOD2 targeted genes were performed using GSE11341 and GSE131425 datasets. Next, primary PASMCs were exposed to CIH environment, and then measured its proliferation, migration and glycolysis by CCK8, EdU assay, wound healing assay, Transwell and western blotting. RESULTS: PLOD2 expression was increased in the lungs of CIH-induced mice and in PASMCs under CIH conditions. Moreover, glycolysis and PI3K/AKT pathway were regulated by PLOD2. Silencing of PLOD2 significantly inhibited the increase of RV/(LV+S) and RVSP, alleviated pathological changes of lung in CIH-induced mice and restrained the proliferation, migration, glycolysis and activation of PI3K/AKT in CIH-induced PASMCs. The inhibitory effects of PLOD2 silencing on PASMC proliferation and migration were accelerated by 2-DG (an inhibitor of glycolysis) and were reversed by lactate (the end product of glycolysis). In addition, the inhibitory effects of PLOD2 silencing on PASMC proliferation, migration and glycolysis were accelerated by PI3K/AKT inhibitor LY294002 and were reversed by the agonist 740Y-P. CONCLUSIONS: Silencing of PLOD2 inhibits PI3K/AKT signaling to limit PASMC glycolysis which allows PASMC proliferation and migration in CIH-induced pulmonary arterial hypertension (PAH).