Integrated multi-omics analysis identified 820 differentially expressed genes, 558 differentially expressed proteins, and 1,377 differential metabolites/lipids, which were mainly enriched in pathways related to inflammation and immunity, cellular signal transduction, ferroptosis, and HIF-1 signaling. TRIM21 emerged as a central molecule exhibiting significant dynamic upregulation in the early (hyperoxic) stage and downregulation in the late (hypoxic) stage of BPD-PH. Further validation in animal models, cellular experiments and clinical samples confirmed a marked elevation of TRIM21, IL-6 and IL-8 expressions in early-stage BPD-PH infants. Mechanistic study revealed that hyperoxia induced TRIM21 upregulation, enhanced NF-κB signaling activation, and promoted PASMC proliferation and migration, while TRIM21 and NF-κB activity was decreased during later disease stages. All these data demonstrate that TRIM21 orchestrated BPD-PH inflammation and vascular remodeling in a dynamic manner of early activation and late inhibition, suggesting TRIM21 as a promising molecular target and providing mechanistic insights for the precise diagnosis and treatment of BPD-PH.