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

Feng Zhou, Xinnan Tang, Kaiquan Li, Nan Lu, Yundong Mao
In: Frontiers in Cell and Developmental Biology · 2026 · vol. 14 , pp. 1805254 · doi:10.3389/fcell.2026.1805254 · PMID:42255479 · PMC13236687 · W7162112053
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Exosomal LINC02701 from active endometriosis follicular fluid promotes granulosa cell apoptosis by interacting with GRP75 to disrupt the GRP75–P53 complex and enhance P53 nuclear accumulation.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-08 ⓘ

The paper studied follicular fluid-derived exosomes from women undergoing IVF who were categorized as having active endometriosis, controlled endometriosis, or no endometriosis, using exosomal RNA sequencing and granulosa cell experiments to define functional effects of disease-associated lncRNAs. The key finding was that LINC02701 is enriched in exosomes from active endometriosis, can enter granulosa cells, suppress proliferation, and promote apoptosis, mediated by disruption of the GRP75–P53 interaction with increased nuclear P53 and downstream activation of apoptotic markers including BAX and PUMA. LINC02701 knockdown reduced apoptosis, and pharmacologic P53 inhibition partially reversed the pro-apoptotic effects of LINC02701. A major caveat is the small, exploratory clinical cohort (24 patients, strict inclusion/exclusion, and the cohort intended mainly for mechanistic association rather than formal biomarker model development), alongside reliance on in vitro granulosa cell models. This paper is centrally about endometriosis — it identifies exosomal LINC02701 in active endometriosis as a driver of granulosa cell apoptosis via the GRP75–P53 axis and links this pathway to impaired early embryo quality.

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Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

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endometriosisinfertility

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