This study investigates sex-specific responses to hyperoxia in the distal lung capillary endothelium, a key factor in bronchopulmonary dysplasia (BPD) development. Using a mouse model, we distinguish between the effects of gonadal hormones and sex chromosome complement on gene expression. They find that males, both chromosomal and gonadal, exhibit more transcriptional changes in response to hyperoxia compared to females. Furthermore, specific biological pathways are identified, and potential drug targets for individualized therapy are proposed, highlighting the importance of understanding sex-specific mechanisms in BPD pathogenesis and treatment.