bims-ovagas 2026-05-10 papers

bims-ovagas

Biomed News

on Ovarian aging and cGAS

Issue of 2026–05–10
thirteen papers selected by
Haiyuan Mu, University of California Berkeley

Age-related upregulation of p16 expression in mouse ovarian somatic cells correlated with reproductive function decline p16 expression and ovarian aging in mice.
Polycomb shapes active chromatin and promoter bivalency during ovarian reserve formation and activation.
Research Hotspots and Emerging Frontiers in Ovarian Aging: A Bibliometric Analysis (2006-2025).
MCM8-9 helicase activity protects primordial germ cell development to prevent premature ovarian insufficiency.
Unravelling Multilayered RNA Modification Networks in Female Reproduction and Obstetric/Gynaecologic Disorders.
Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissues: impact and legacy two decades latter.
Ypel5 preserves female fertility by regulating folliculogenesis and oocyte maturation.
Inhibition of oogenic JNK preserves fertility and ovarian hormones during DNA-damaging cancer therapy.
Prolonged oscillating preoptic area kisspeptin neuron activity underlies the preovulatory luteinizing hormone surge in mice.
Molecular Mechanisms of Dysregulated LH and FSH Secretion in Human Reproductive Failure.
Cohesin variants associated with human reproductive and developmental disorders.
A human CEP120 gene variant impairs meiotic spindle building causing aneuploidy†.
Endometrial NCOR1 deficiency contributes to implantation failure in endometriosis-associated infertility.

PLoS One. 2026 ;21(5): e0348870

Age-related upregulation of p16 expression in mouse ovarian somatic cells correlated with reproductive function decline p16 expression and ovarian aging in mice.

Yorino Sato, Yuta Kawagoe, Kazuhiro Kawamura.

Female reproductive aging is a major clinical challenge associated with declining fertility and increased pregnancy complications. The urgent clinical need for developing reliable biomarkers to evaluate ovarian aging has become increasingly evident. Cellular senescence, marked by p16, contributes to age-related tissue dysfunction. However, the relationship between p16 levels and ovarian aging remains poorly understood. Age-related changes in p16 levels across multiple tissues in ICR mice were examined in ICR mice at 4, 30, 45, and 60 weeks of age using qRT-PCR, ELISA, and immunohistochemistry. Cell-type specific p16 levels were analyzed in isolated ovarian cells. Reproductive function was assessed through superovulation, in vitro fertilization, and embryo transfer experiments. p16 mRNA levels increased progressively with age in ovarian tissue (6.8-fold increase at 60 weeks vs. 4 weeks, P < 0.05), with corresponding increases in p16 protein levels. Among tissues examined, ovaries, kidneys, liver, uterus, spleen, and pancreas showed significant age-related p16 upregulation, while brain, heart, and lung did not. Cell-type analysis revealed that somatic cells exhibited pronounced p16 upregulation with age (cumulus cells: 3.2-fold, granulosa cells: 4.6-fold, theca cells: 2.8-fold increase), whereas oocytes and blastocysts showed no significant changes. Ovulation numbers decreased significantly with age (42.3 ± 3.1 vs. 15.6 ± 1.9 oocytes in young vs. aging mice), but fertilization rates and early embryo development remained unaffected. However, post-implantation outcomes deteriorated substantially, with implantation rates declining from 78.4% to 38.1% and live birth rates from 82.3% to 43.2% in aging mice at 60 weeks of age. Age-related upregulation of p16 in ovarian somatic cells, but not in oocytes, correlated with declining reproductive function, particularly affecting post-implantation development. These findings suggest that somatic cell senescence may contribute to age-related declines in oocyte competence, leading to fertility decline with aging.

DOI: https://doi.org/10.1371/journal.pone.0348870
bioRxiv. 2026 Apr 25. pii: 2026.04.22.720278. [Epub ahead of print]

Polycomb shapes active chromatin and promoter bivalency during ovarian reserve formation and activation.

Mengwen Hu, Yasuhisa Munakata, Yu-Han Yeh, Neil Hunter, Richard M Schultz, Satoshi H Namekawa.

The ovarian reserve, a finite pool of long-lived non-growing oocytes established at birth, determines female reproductive lifespan, yet how these oocytes establish long-term quiescence while retaining the capacity for future growth and embryogenesis remains poorly understood. Here, we define a regulatory logic by which Polycomb repressive complexes shape stage-specific active chromatin remodeling during ovarian reserve formation and early oocyte growth. During ovarian reserve formation, H3K27ac, an active promoter- and enhancer-associated mark, undergoes extensive genome-wide redistribution. A key feature of this transition is CpG island promoter remodeling, in which many loci lose H3K27ac while gaining PRC1-dependent H2AK119ub, a repressive mark. This early reprogramming is followed during oocyte growth by acquisition of PRC2-dependent H3K27me3, de novo establishment of bivalent promoters, and protection of promoter regions from de novo DNA methylation. Oocyte growth is also accompanied by broad gains in both H3K27ac and H3K4me3, an active promoter-associated mark. Analyses of PRC1- and PRC2-deficient oocytes reveal unequal Polycomb contributions: PRC2 broadly constrains H3K27ac, whereas PRC1 more selectively shapes genome-wide H3K27ac redistribution and restricts H3K4me3 accumulation at bivalent promoters. Together, these findings identify staged active chromatin remodeling as an integral feature of perinatal oocyte development and reveal that Polycomb shapes chromatin state transitions as oocytes enter quiescence and become poised for future growth.
One-Sentence Summary: Polycomb repressive complexes shape stage-specific active chromatin remodeling to establish quiescence and future promoter states during ovarian reserve formation and early oocyte growth.

DOI: https://doi.org/10.64898/2026.04.22.720278
Endocr Metab Immune Disord Drug Targets. 2026 Apr 28.

Research Hotspots and Emerging Frontiers in Ovarian Aging: A Bibliometric Analysis (2006-2025).

Qingquan Gong, Wenhong Ma, Chao Yang, Dingyu Liang, Yifu Wang, Yihua Yang, Mingyou Dong.

   INTRODUCTION: Ovarian aging has a critical impact on women's fertility and overall health. This study uses bibliometric methods to analyze the current state of research in the field of natural ovarian aging and to identify emerging trends.
METHODS: This study analyzed 653 publications from the Web of Science Core Collection (2006-2025). Using VOSviewer and CiteSpace software, the authors visualized collaboration networks and identified research hotspots through co-occurrence and co-citation analyses.
RESULTS: Annual publications in the field of natural ovarian aging showed a significant upward trend; China and the United States were the main contributors to this research area. Huazhong University of Science and Technology and Nanjing Medical University were among the institutions with the highest number of publications. Wang SX was the author with the most publications, while Broekmans FJ was the most cited scholar. Human Reproduction was a core journal in this field. Keyword co-occurrence and reference co-citation analyses indicated that mitochondrial dysfunction, cellular senescence, inflammation, fibrosis, and multi-omics research were the research hotspots and frontiers during the study period.
DISCUSSION: The surge in keywords and citations suggests that the field is undergoing a fundamental shift from clinical phenotype studies to the exploration of molecular mechanisms. Findings in hotspot areas such as fibrosis and senescent cell clearance provide potential therapeutic targets for future clinical translation.
CONCLUSION: This study employs bibliometric methods to map the current state of research, core themes, and emerging frontiers in the field of natural ovarian aging. The results offer researchers valuable insights into understanding the development trends in this field and guiding future research.

Keywords:  Ovarian Aging; bibliometric analysis; cellular senescence; fibrosis; inflammation; mitochondrial dysfunction; multi-omics

DOI:  https://doi.org/10.2174/0118715303441084260119050045
Proc Natl Acad Sci U S A. 2026 May 12. 123(19): e2535910123

MCM8-9 helicase activity protects primordial germ cell development to prevent premature ovarian insufficiency.

Xiaofei Jiao, Zhifang Li, Zhenghui Tang, Jun Xu, Lin-Yu Lu, Yidan Liu.

  MCM8 and MCM9 form a hexameric helicase critical for homologous recombination (HR). While their variants are strongly associated with premature ovarian insufficiency (POI), with many clustering within their AAA+ ATPase domains, the requirement for their helicase activity remains unknown. Here, we show that MCM8-9's helicase activity is essential for ovarian reserve preservation and POI prevention. Using a series of helicase-deficient mouse models, we demonstrate that this activity is dispensable for meiotic recombination but critically required for mitotic HR and primordial germ cell (PGC) development. The two distinct ATPase active sites of MCM8-9 exhibit marked functional asymmetry, a property regulated by residues within their Walker B motifs. Despite this asymmetry, both ATPase active sites are equally essential for MCM8-9's function in HR, PGC development, ovarian reserve preservation, and POI prevention. Our findings establish a direct mechanistic link between compromised MCM8-9 helicase activity and POI pathogenesis through its essential role in PGC development.

Keywords:  helicase; homologous recombination; premature ovarian insufficiency; primordial germ cell

DOI:  https://doi.org/10.1073/pnas.2535910123
Biomolecules. 2026 Apr 13. pii: 571. [Epub ahead of print]16(4):

Unravelling Multilayered RNA Modification Networks in Female Reproduction and Obstetric/Gynaecologic Disorders.

Yujie Kuai, Yanjun Yi, Xinyu Li, Zhuangping Wang, Yan Zheng, Yuxuan Li, Yulin Li.

  Background/Objective: RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), 7-methylguanosine (m7G), N1-methyladenosine (m1A), pseudouridine (Ψ), N4-acetylcytidine (ac4C), 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) and adenosine-to-inosine (A-to-I) editing, constitute a critical layer of post-transcriptional regulation that influences RNA stability, splicing, translation and degradation. This review aims to systematically summarise the current understanding of the molecular mechanisms and regulatory networks of RNA modifications in the female reproductive physiology and to evaluate their pathological implications in obstetric and gynaecologic disorders. Methods: We conducted a comprehensive literature review, synthesising findings from high-throughput sequencing studies, functional experiments and clinical investigations. The review integrates evidence across multiple RNA modification types, their regulatory enzymes (writers, erasers and readers) and their roles in physiological processes (germ cell development, oocyte maturation, embryogenesis and endometrial function) and pathological conditions (gynaecologic cancers, preeclampsia, endometriosis, polycystic ovary syndrome and premature ovarian insufficiency). Results: RNA modifications function as dynamic and reversible regulators that orchestrate key reproductive events, including primordial germ cell differentiation, oocyte meiosis, the maternal-to-zygotic transition, the establishment of uterine receptivity, and placental development. These modifications operate through coordinated writer-eraser-reader networks that fine tune transcripts' stability, translation efficiency and RNA decay. The dysregulation of these epitranscriptomic networks is strongly implicated in the pathogenesis of gynaecologic malignancies (cervical, ovarian, endometrial cancers and choriocarcinoma), pregnancy-related disorders (preeclampsia, gestational diabetes mellitus and recurrent miscarriage), reproductive endocrine disorders (polycystic ovary syndrome and premature ovarian insufficiency) and benign gynaecological conditions (endometriosis and adenomyosis). Emerging evidence also reveals complex crosstalk among RNA modifications, such as cooperative interactions between m6A and m5C in translation regulation and antagonistic relationships between m6A and A-to-I editing. Conclusions: RNA modifications represent an essential and multifaceted regulatory layer in female reproduction, with broad implications for disease pathogenesis. Their unique reversibility and context-dependent functions offer promising opportunities for the development of diagnostic biomarkers and targeted therapeutic interventions. Future researchers should prioritise integrated multi-omics approaches, enhanced human-relevant models and clinical translation to fully realise the potential of epitranscriptomic medicine in reproductive health.

Keywords:  RNA modification; female reproduction; gynaecological disease; gynaecological oncology; obstetrical; pregnancy-related diseases; reproductive endocrine diseases; reproductive physiology

DOI:  https://doi.org/10.3390/biom16040571
Hum Reprod. 2026 May 01. 41(5): 643-646

Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissues: impact and legacy two decades latter.

Claus Yding Andersen, Marie-Madeleine Dolmans, Erik Ernst.

DOI: https://doi.org/10.1093/humrep/deag026
Cell Death Differ. 2026 May 05.

Ypel5 preserves female fertility by regulating folliculogenesis and oocyte maturation.

Ling Ding, Qianying Guo, Yao Li, Fanqing Xu, Qiang Liu, Shaogang Qin, Ying Kuo, Jie Qiao, Peng Yuan, Liying Yan.

Maintaining the primordial follicle pool and precisely regulating folliculogenesis are critical for female fertility. Despite advances in understanding ovarian development, the molecular mechanisms safeguarding follicle survival and oocyte maturation remain incompletely defined. Here, we identify YPEL5 as an essential regulator of folliculogenesis and oocyte development. Using an oocyte-specific conditional knockout (cKO) mouse model, we demonstrate that Ypel5 deletion causes complete female infertility, characterized by accelerated depletion of the primordial follicle pool, defective antral follicle formation, and impaired oocyte maturation. Loss of Ypel5 results in increased DNA damage, disrupted mitochondrial homeostasis, elevated oxidative stress, and ultimately triggers apoptotic depletion of primordial follicle oocytes. Moreover, Ypel5-deficient oocytes exhibit severe abnormalities in spindle organization and mitochondrial distribution, culminating in defective oocyte maturation. Collectively, these findings establish YPEL5 as a critical regulator of follicle development and oocyte maturation, and provide mechanistic insights into the molecular basis of female infertility.

DOI: https://doi.org/10.1038/s41418-026-01744-3
bioRxiv. 2026 May 01. pii: 2026.04.28.721450. [Epub ahead of print]

Inhibition of oogenic JNK preserves fertility and ovarian hormones during DNA-damaging cancer therapy.

Wenlong Zhao, Jiyang Zhang, Yingnan Bo, Yingzheng Wang, Mi Ran Choi, Shichao Liu, Qiang Zhang, So-Youn Kim, Shuo Xiao.

Primary ovarian insufficiency (POI) and related infertility, early menopause, and endocrine disorders due to hormonal deficiency are major side effects in young female cancer patients undergoing cancer therapy. Current strategies preserving the fertility and hormonal functions of the ovary remain imperfect due to concerns of feasibility, efficacy, or safety. Herein, we identified c-Jun N-terminal kinase (JNK) as a pivotal regulator of the DNA damage response (DDR) signaling in oocytes of primordial follicles in response to DNA-damaging cancer therapy. Using pharmacological JNK inhibition and a genetically modified mouse model with oocyte-specific JNK deletion, together with histological, bioinformatic, and molecular approaches, we demonstrated that JNK inhibition prevented chemotherapy-induced oocyte apoptosis and POI, and preserved long-term reproductive cycles and fertility. Mechanistically, JNK was activated in response to chemotherapy-induced DNA damage in oocytes of primordial follicles, causing activation of transcription factor TAp63α and subsequent oocyte apoptosis, ultimately resulting in diminished ovarian reserve and POI. A more clinically relevant breast cancer-bearing mouse model revealed that JNK inhibition preserved the ovarian reserve without compromising anti-cancer efficacy of chemotherapy. Together, our study identifies oocyte-intrinsic JNK as a promising target for developing ovarian protectants and safeguarding reproductive health and fertility in young female cancer survivors.

DOI: https://doi.org/10.64898/2026.04.28.721450
Elife. 2026 May 07. pii: RP109215. [Epub ahead of print]14

Prolonged oscillating preoptic area kisspeptin neuron activity underlies the preovulatory luteinizing hormone surge in mice.

Ziyue Zhou, Cheng-Yu Huang, Allan Edward Herbison.

  The population of kisspeptin neurons located in the rostral periventricular area of the third ventricle (RP3V) is thought to have a key role in generating the GnRH surge that triggers ovulation. Using a modified GCaMP fibre photometry procedure, we have been able to record the in vivo population activity of RP3VKISS neurons across the estrous cycle of female mice. A marked increase in GCaMP activity was detected beginning on the afternoon of proestrus that lasted in total for 13±1 hr. This was comprised of slow baseline oscillations with a period of 91±4 min associated with high-frequency rapid transients. Very little oscillating baseline or transient activity was detected at other stages of the estrous cycle. Concurrent blood sampling showed that the peak of the LH surge occurred 3.5±1.1 hr after the first baseline RP3VKISS neuron baseline oscillation on the afternoon of proestrus. The time of onset of RP3VKISS neuron oscillations varied between mice and across subsequent proestrous stages in the same mice. To assess the impact of estradiol on RP3VKISS neuron activity, mice were ovariectomized and given an incremental estradiol replacement regimen. Minimal patterned GCaMP activity was found in OVX mice, and this was not changed acutely by any of the estradiol treatments. However, on the afternoon of the expected LH surge, the same oscillating baseline activity with associated transients occurred for 7.1±0.5 hr. These observations reveal an unexpected prolonged oscillatory pattern of RP3VKISS neuron activity that is dependent on estrogen and underlies the preovulatory LH surge as well as potentially other facets of reproductive behavior.

Keywords:  GnRH; LH surge; estrogen; kisspeptin; mouse; neuroscience; photometry

DOI:  https://doi.org/10.7554/eLife.109215
Biomedicines. 2026 Mar 31. pii: 789. [Epub ahead of print]14(4):

Molecular Mechanisms of Dysregulated LH and FSH Secretion in Human Reproductive Failure.

Athanasios Zikopoulos, Efthalia Moustakli, Anastasios Potiris, Vasilis Sebastian Paraschos, Periklis Katopodis, Pavlos Machairoudias, Panagiotis Antsaklis, Nikolaos Kathopoulis, Ismini Anagnostaki, Sofoklis Stavros.

  Several reproductive issues in both men and women are caused by changes in the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). For males to sustain spermatogenesis and Leydig cell function, and for females to ensure orderly folliculogenesis, ovulation, and ovarian steroidogenesis, precise coordination of LH and FSH secretion is necessary. Pituitary responsiveness, the frequency or amplitude of gonadotropin-releasing hormone pulses, or the dysregulation of feedback signals mediated by sex steroids and inhibins all disrupt the balance between LH and FSH secretion. Oligozoospermia, luteal-phase abnormalities, anovulation, or complete spermatogenic failure are possible clinical signs of these alterations. In addition to functional neuroendocrine disturbances, emerging genetic and epigenetic evidence, including pathogenic variants in genes such as gonadotropin-releasing hormone receptor, kisspeptin, kisspeptin receptor, luteinizing hormone beta subunit, follicle-stimulating hormone beta subunit, follicle-stimulating hormone receptor, and luteinizing hormone/choriogonadotropin receptor, has highlighted the role of inherited and acquired molecular defects in disrupting gonadotropin regulation. This narrative review synthesizes contemporary mechanistic, clinical, translational, and genetic evidence elucidating how dysregulated secretion of LH and FSH contributes to reproductive dysfunction. The molecular processes that regulate gonadotropin synthesis and release, as well as neuroendocrine regulation, gene-level determinants of hypothalamic-pituitary-gonadal (HPG) axis dysfunction, and the clinical phenotypes that result from their disruption, are all given special attention. We conclude with a discussion of new treatment strategies that target local intragonadal regulators to enhance gametogenic capacity, modulate gonadotropin signaling, or restore physiological gonadotropin-releasing hormone (GnRH) pulsatility, with consideration of how genetic insights may inform personalized therapeutic approaches.

Keywords:  GNRHR signaling; GnRH pulsatility; KNDy neurons; LHB and FSHB transcription; SMAD pathway; activin–inhibin axis; hypogonadotropic hypogonadism; polycystic ovary syndrome

DOI:  https://doi.org/10.3390/biomedicines14040789
J Genet Genomics. 2026 May 06. pii: S1673-8527(26)00156-6. [Epub ahead of print]

Cohesin variants associated with human reproductive and developmental disorders.

Yuanyuan Liu, Jun Zhou.

  The cohesin complex is an evolutionarily conserved multi-subunit protein assembly essential for sister chromatid cohesion, meiotic recombination, DNA double-strand break repair, and transcriptional regulation. Pathogenic variants in its subunits are implicated in a spectrum of reproductive and developmental disorders, including non-obstructive azoospermia, premature ovarian insufficiency, reproductive aging, aneuploidy, Cornelia de Lange syndrome, Roberts syndrome, cancer, and neuro-psychiatric disease. Consequently, identifying cohesin mutations is a priority for precision diagnostics and personalized medicine. This review systematically summarizes the cohesin variants linked to these pathologies, exploring their molecular mechanisms and clinical manifestations. A deeper understanding of these variants is crucial not only for deciphering disease etiology but also for guiding the development of targeted diagnostic strategies and therapeutic interventions, ultimately improving patient management and outcomes.

Keywords:  Chromosome segregation; Cohesin; Developmental diseases; Genetic variants; Reproductive disorders

DOI:  https://doi.org/10.1016/j.jgg.2026.04.024
Biol Reprod. 2026 May 07. pii: ioag094. [Epub ahead of print]

A human CEP120 gene variant impairs meiotic spindle building causing aneuploidy†.

Marlena Duke, Cecilia S Blengini, Sophia Maddocks, Mansour Aboelenain, Christine Prorock-Rogers, Karen Schindler.

  Infertility is increasing, leading more women to seek assisted reproduction treatments than ever before. One of the main causes of infertility and pregnancy loss is aneuploidy, an incorrect number of chromosomes in the embryo or developing fetus, which hinders normal development. Aneuploidy overwhelmingly arises from the missegregation of chromosomes during the maternal meiotic divisions that produce haploid oocytes (or eggs). Variants of genes involved in spindle building are of primary interest when searching for genetic causes of aneuploidy because the oocyte meiotic spindle is responsible for faithful chromosome segregation. We previously identified a genetic variant in a human centrosome gene, CEP120, as associated with high embryonic aneuploidy. To evaluate the functional significance of this genetic variant, we generated a knock-in mouse model and found that female mice had reduced fertility and increased egg aneuploidy. By assessing microtubule re-establishment after cold temperature exposure and warming after vitrification, we found that oocytes from mice harboring the genetic variant had reduced microtubule nucleation efficiency. Because mouse and human oocytes present differences in spindle building mechanism, we modified mouse oocyte spindle building assembly by pericentrin depletion to better mimic human oocytes and found that aneuploidy levels significantly increase in CEP120 variant eggs. Although PGT-A allows the deselection of aneuploid embryos, the development of biomarkers for predisposition to aneuploidy could be used to identify subfertile patients and model their aneuploid risk. Therefore, our data indicate that patients harboring common genetic variants in CEP120 may require additional counseling when considering egg cryopreservation procedures.

Keywords:  CEP120; IVF; MTOC; aneuploidy; gene variants; meiosis; oocyte; spindle; vitrification

DOI:  https://doi.org/10.1093/biolre/ioag094
iScience. 2026 May 15. 29(5): 115727

Endometrial NCOR1 deficiency contributes to implantation failure in endometriosis-associated infertility.

Loan Thi Kim Nguyen, Dinh Nam Tran, Johan Auwerx, Harini Raghu Kumar, Steven L Young, Bruce A Lessey, Ripla Arora, Jung-Yoon Yoo, Tae Hoon Kim, Jae-Wook Jeong.

  Endometriosis-associated infertility is a complex condition in which the presence of endometrial-like tissue disrupts implantation and early pregnancy. Epigenetic regulators are critical for implantation and decidualization, yet their contribution to endometriosis-associated infertility remains incompletely understood. Nuclear receptor corepressor 1 (NCOR1), an epigenetic coregulator of steroid hormone signaling, has an incompletely defined role in endometriosis and early pregnancy. We show that NCOR1 expression is significantly reduced in the eutopic endometrium of infertile women with endometriosis. Using a conditional uterine Ncor1-knockout mouse model (Pgr cre/+ Ncor1 f/f ), we demonstrate that NCOR1 loss is associated with increased ectopic lesion burden, implantation failure, defective decidualization, and severe subfertility, despite normal ovarian hormone production. NCOR1 deficiency was associated with disrupted progesterone-responsive signaling and endometrial receptivity. Together, these findings identify NCOR1 as an important regulator of endometrial function during early pregnancy and support an association between reduced NCOR1 expression and endometriosis-associated infertility.

Keywords:  Epigenetics; Molecular genetics; Molecular mechanism of gene regulation

DOI:  https://doi.org/10.1016/j.isci.2026.115727