Exosomal MiR-653-3p Alleviates Hypoxic-Ischemic Brain Damage via the TRIM21/p62/Nrf2/CYLD Axis.

ABSTRACT

Hypoxic-ischemic brain damage (HIBD) is the main risk factor for preterm infants' brain injury. Exosomes originating from bone marrow mesenchymal stem cells (BMSCs) have a protective effect against hypoxic-ischemic conditions. However, it remains to be elucidated whether exosome carrying miR-653-3p released by BMSC exerts specific functions in HIBD. Based on the analyses of high-throughput miRNA sequencing and RT-qPCR data, the low expression of miR-653-3p was identified in HIBD rats and oxygen-glucose deprivation (OGD)-induced BMSCs and HMC3 cells. In vitro functional experiments indicated that exosomal miR-653-3p derived from BMSC alleviated OGD-induced HMC3 cell damage. Mechanistically, miR-653-3p targeted TRIM21, regulating p62 ubiquitination to modulate the activity of Keap1/Nrf2 pathway. Furthermore, Nrf2 transcriptionally activated CYLD to inhibit the NF-κB pathway in HIBD. Rescue experiments verified that miR-653-3p could mitigate OGD-induced HMC3 cellular injury through CYLD. Finally, in vivo animal experiments validated the alleviation of HIBD in model rats treated with BMSC-derived miR-653-3p. Our study demonstrated that exosomal miR-653-3p from BMSC alleviates HIBD by inactivating the NF-κB pathway through the TRIM21/p62/Nrf2/CYLD axis.