EIF4A3-Induced Exosomal circLRRC8A Alleviates Granulosa Cells Senescence Via the miR-125a-3p/NFE2L1 axis

Premature ovarian failure (POF) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Mesenchymal stromal cells-derived exosomes (MSCs-Exos) have an essential role in the treatment of reproductive disorders, particularly POF. However, the biological function and therapeutic mechanism of MSCs exosomal circRNAs in POF remain to be determined. Here, with bioinformatics analysis and functional assays, circLRRC8A was found to be downregulated in senescent granulosa cells (GCs) and acted as a crucial factor in MSCs-Exos for oxidative damage protection and anti-senescence of GCs in vitro and in vivo. Mechanistic investigations revealed that circLRRC8A served as an endogenous miR-125a-3p sponge to downregulate NFE2L1 expression. Moreover, eukaryotic initiation factor 4A3 (EIF4A3), acting as a pre-mRNA splicing factor, promoted circLRRC8A cyclization and expression by directly binding to the LRRC8A mRNA transcript. Notably, EIF4A3 silencing reduced circLRRC8A expression and attenuated the therapeutic effect of MSCs-Exos on oxidatively damaged GCs. This study demonstrates a new therapeutic pathway for cellular senescence protection against oxidative damage by delivering circLRRC8A-enriched exosomes through the circLRRC8A/miR-125a-3p/NFE2L1 axis and paves the way for the establishment of a cell-free therapeutic approach for POF. CircLRRC8A may be a promising circulating biomarker for diagnosis and prognosis and an exceptional candidate for further therapeutic exploration. Graphical Abstract