MiR-17-5p protects neonatal mice from hypoxic-ischemic brain damage by targeting Casp2

•This study presents a novel miRNA that is involved in the regulation of the development of hypoxic-ischemic brain damage.•We find that Casp2 is a target gene of miR-17-5p.•Our study firstly demonstrates that miR-17-5p protects neonatal mice from hypoxic-ischemic brain damage by targeting Casp2, providing a theoretical basis for hypoxic-ischemic brain damage treatment. Hypoxia-ischemia brain damage (HIBD) is a leading cause of neonatal death worldwide, which significantly influences the development of newborns; however, effective treatment strategies remain limited. Recent studies have discovered that microRNAs (miRNAs) play essential roles in the progression of HIBD. Our study was designed to explore whether miR-17-5p was involved in the pathological development of HIBD. In our study, HIBD mouse experimental model was established by carotid artery ligation combined with a hypoxic environment. RT-qPCR and western blot analyses found that Casp2 was high expressed while miR-17-5p was poorly expressed in the cerebral cortical tissue of HIBD mice. Knockdown of Casp2 significantly alleviated brain injury and cell apoptosis. Additionally, the luciferase reporter assay confirmed that miR-17-5p targeted the 3′ UTR of Casp2 and negatively regulated Casp2 expression. The rescue experiment demonstrated that miR-17-5p mimic significantly relieved brain tissue damage and improved memory ability in the HIBD mouse model, while these functions of miR-17-5p were blocked by overexpression of Casp2. In summary, our results indicated that miR-17-5p exerted protective effects on HIBD by targeting Casp2.