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Lung ischemia-reperfusion (I/R) injury is a common complication following lung transplantation and cardiac surgery. This study aimed to investigate the role and underlying mechanisms involving Neurogenic locus notch homologue protein 1 (Notch1) signalling and microRNA-485 (miR-485) of hypoxia-inducible factor 1-alpha (HIF1α) in protecting pulmonary microvascular endothelial cells (PMVECs) against I/R-induced injury. We found that overexpression of HIF1α significantly increased cell viability and decreased apoptosis in hypoxia/reoxygenation (H/R)-treated PMVECs, while knockdown or inhibition of HIF1α had the opposite effects. Moreover, HIF1α overexpression activated the Notch1 signalling pathway by upregulating Hes1 mRNA expression and Hes1 promoter activity. Conversely, HIF1α knockdown or inhibition inhibited Notch1 signalling. Furthermore, HIF1α overexpression alleviated H/R-induced mitophagy and mitochondrial dysfunction. On the other hand, HIF1α knockdown or inhibition aggravated mitophagy and mitochondrial dysfunction. We also found that HIF1α transcriptionally activated the expression of miR-485. Overexpression of miR-485 reversed the detrimental effects of HIF1α knockdown or inhibition on cell viability, apoptosis, Hes1 expression and mitophagy levels in H/R-treated PMVECs. Additionally, we identified NUMB endocytic adaptor protein (Numb) mRNA as a direct target of miR-485, and miR-485 overexpression suppressed Numb expression in PMVECs. In conclusion, these results suggest that targeting the HIF1α-miR-485-Numb axis may be a potential therapeutic strategy for attenuating lung I/R injury.