The Age‐Associated Long Noncoding RNA lnc81 Regulates Ovarian Granulosa Cell Proliferation and Apoptosis Through TEAD2‐CCN1/2 Pathway in Mice

Ovarian granulosa cells (GCs) are pivotal for follicular homeostasis, and their dysregulated apoptosis drives age‐related ovarian aging. The Hippo signaling pathway, modulated by long noncoding RNAs (lncRNAs), is implicated in regulating GCs proliferation and ovarian aging. TEAD2 (Transcriptional Enhanced Associate Domain 2), a key downstream transcription factor of the Hippo signaling pathway, plays a critical role in regulating cell proliferation, apoptosis, and embryonic stem cell self‐renewal. However, the precise molecular mechanisms by which lncRNAs influence the Hippo pathway in GCs are not fully understood. Through comprehensive RNA‐seq analysis of ovarian tissues across three distinct age groups (3‐, 11‐, and 17‐month‐old mice), we identified lnc81 as a senescence‐associated lncRNA that physically interacts with TEAD2. RNA immunoprecipitation (RIP) assays demonstrated direct binding between lnc81 and TEAD2, while subcellular fractionation coupled with qRT‐PCR revealed predominant nuclear localization of lnc81 in granulosa cells (GCs). Importantly, lnc81 expression exhibited a progressive, age‐dependent elevation during ovarian aging. Functional characterization showed that lnc81 knockdown in GCs significantly: (i) Inhibited cellular proliferation (as evidenced by decreased Pcna expression). (ii) Promoted apoptosis (indicated by increased BAX/BCL‐2 ratio and elevated TUNEL‐positive cells). Mechanistically, while lnc81 depletion upregulated CCN1/CCN2 protein levels, it did not affect TEAD2 expression, suggesting that lnc81 regulates TEAD2 transcriptional activity rather than modulating its protein stability. Our findings highlight lnc81 as a nuclear lncRNA that interacts with TEAD2 to amplify CCN1/CCN2 signaling, thereby promoting GC apoptosis and ovarian aging. This mechanistic insight positions lnc81 as a potential biomarker for age‐related ovarian decline and a candidate target for therapeutic intervention.

• Publication year

  2025

• Venue

  Journal of Cellular Physiology

• Publication date

  2025-09-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1002/jcp.70090PMID 40928008
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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