Follicular fluid-derived exosomal LINC02701 promotes granulosa cell apoptosis through the GRP75-P53 axis in active...

Endometriosis (EMs)-associated infertility has been linked to alterations in the follicular microenvironment; however, the role of exosomal long non-coding RNAs (lncRNAs) in granulosa cell dysfunction remains incompletely understood.

Follicular fluid-derived exosomes were isolated from patients with active endometriosis (EMs_A), controlled endometriosis (EMs_C), and non-endometriosis controls. Transcriptomic sequencing was performed to identify differentially expressed exosomal lncRNAs. Functional assays, loss-of-function experiments, mechanistic analyses, and pharmacological inhibition studies were conducted in granulosa cells.

LINC02701 was identified as one of the most significantly enriched exosomal lncRNAs in active endometriosis. Functional assays demonstrated that LINC02701 can be transferred into granulosa cells, where it suppresses proliferation and promotes apoptosis. Knockdown of LINC02701 attenuated granulosa cell apoptosis, whereas pharmacological inhibition of P53 partially reversed the pro-apoptotic effects induced by LINC02701. Mechanistically, LINC02701 directly interacted with GRP75, disrupted the GRP75-P53 interaction, enhanced nuclear accumulation of P53, and activated downstream apoptotic signaling, including BAX and PUMA. Clinically, EMs_A patients exhibited elevated CA125 levels, increased uterosacral ligament tenderness, and reduced Day-3 high-quality embryo rates, which were consistent with the observed cellular phenotypes.

These findings suggest that exosomal LINC02701 may contribute to granulosa cell dysfunction through modulation of the GRP75-P53 axis and may be associated with impaired early embryo quality in active endometriosis, highlighting its potential as a candidate biomarker for EMs-associated infertility.