bims-ovagas Biomed News
on Ovarian aging and cGAS
Issue of 2026–07–05
twelve papers selected by
Haiyuan Mu, University of California Berkeley
  1. The immune microenvironment: a key regulator of ovarian function during ovarian aging.
  2. Mouse offspring conceived by in vitro fertilization exhibit accelerated reproductive aging through early ovarian failure.
  3. Targeting interleukin-11 to slow ovarian aging.
  4. Editorial: Ovarian aging: pathophysiology and recent development of maintaining ovarian reserve, volume IV.
  5. Mitochondria as Integrative Regulators of Ferroptosis in the Female Reproductive System.
  6. Modulating IL-11-dependent matrix stiffness to delay ovarian aging.
  7. A Designed Ankyrin Repeat Protein (DARPin) Targeting EGFR Inhibits Ovulation and Enables a Novel Platform for Studying Ovarian Biology and Pathophysiology.
  8. Spatial Transcriptomics in Ovarian Biology Technologies, Computational Challenges, and Biological Insights.
  9. Female reproductive dysfunction and transgenerational consequences following prolonged spaceflight exposure.
  10. Toll-like Receptor 4 Knockout Mice are Protected Against PMOS-like Pathogenesis.
  11. Understanding GnRH: local systems, signalling mechanisms and implications in female health.
  12. Illuminating aging with multimodal optical metabolic imaging.
  1. Front Immunol. 2026 ;17 1857242
    The immune microenvironment: a key regulator of ovarian function during ovarian aging.
    Tingting Lin, Wei Zhao, Yaoqing Xie, Jianyong Xu, Su Liu, Ling Hong, Jianwen Mao, Chunyu Huang.
      The ovary is a highly dynamic organ characterized by intense biosynthetic activity, cyclical tissue remodeling, and elevated metabolic flux. Within this demanding milieu, precise immune regulation is paramount: tightly coordinated tissue remodeling by innate immunity and vigilant immune surveillance by the adaptive system are critical for maintaining ovarian homeostasis. Mounting evidence identifies dysregulation of the local ovarian immune microenvironment as a core driver of functional decline. This review synthesizes current knowledge on how the ovarian immune microenvironment, in concert with endocrine signals, orchestrates key phases of oocyte development and follicular maturation. We then delineate the immune signatures underpinning physiological ovarian aging and pathological premature ovarian insufficiency, highlighting the mechanistic continuum between these conditions. Finally, we systematically review emerging immunomodulatory interventions targeting the ovarian immune microenvironment, including strategies that restore Treg/Th17 balance, modulate macrophage polarization, and employ mesenchymal stem cells or platelet-rich plasma to remodel the immune niche. By integrating these mechanistic and therapeutic insights, this review aims to establish a coherent theoretical framework and future research directions for developing novel ovarian-protective interventions designed to improve reproductive outcomes and long-term health in aging women and those with POI.
    Keywords:  fertility preservation; immune-targeted therapy; ovarian aging; ovarian immune microenvironment; premature ovarian insufficiency
    DOI:  https://doi.org/10.3389/fimmu.2026.1857242
  2. J Clin Invest. 2026 Jun 30. pii: e201633. [Epub ahead of print]
    Mouse offspring conceived by in vitro fertilization exhibit accelerated reproductive aging through early ovarian failure.
    Eric A Rhon-Calderon, Cassidy N Hemphill, Alexandra J Savage, Ana Domingo-Muelas, Zhengfeng Liu, Christopher J Krapp, Laren Riesche, Nicolas Plachta, Richard M Schultz, Marisa S Bartolomei.
      Reproductive aging is characterized by a progressive decline of reproductive function, with broad implications for overall health and longevity. Environmental factors, including assisted reproductive technologies (ART), can accelerate reproductive aging by promoting premature ovarian failure in females. In vitro fertilization (IVF) though widely used and generally considered safe, has been associated with lasting effects on offspring health. Using a mouse model that closely approximates human IVF, we demonstrated that IVF accelerates reproductive aging in female offspring by inducing premature ovarian failure. IVF-conceived females exhibited altered ovarian function, reduced follicle reserve, disrupted endocrine profiles, and transcriptomic and epigenetic changes consistent with premature reproductive decline. These findings reveal long-term consequences of IVF on female reproductive health and highlight the need to understand how early-life interventions influence reproductive longevity.
    Keywords:  Development; Embryonic development; Epigenetics; Reproductive biology; Transcriptomics
    DOI:  https://doi.org/10.1172/JCI201633
  3. Nat Aging. 2026 Jul 02.
    Targeting interleukin-11 to slow ovarian aging.
    Stuart A Cook.
      
    DOI:  https://doi.org/10.1038/s43587-026-01137-8
  4. Front Endocrinol (Lausanne). 2026 ;17 1888968
    Editorial: Ovarian aging: pathophysiology and recent development of maintaining ovarian reserve, volume IV.
    Osamu Wada-Hiraike, Michio Kitajima, Antonio Simone Laganà.
      
    Keywords:  assisted reproductive technology; diminished ovarian reserve; fertility preservation; oocyte quality; ovarian aging; ovarian reserve; oxidative stress; primary ovarian insufficiency
    DOI:  https://doi.org/10.3389/fendo.2026.1888968
  5. Biol Reprod. 2026 Jun 27. pii: ioag132. [Epub ahead of print]
    Mitochondria as Integrative Regulators of Ferroptosis in the Female Reproductive System.
    Isil Yenigun, Nazli Ece Huner, Aylin Yaba.
      Mitochondrial function is fundamental to female reproductive physiology, supporting follicular development, oocyte maturation, and endometrial remodeling. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a potential contributor to reproductive dysfunction under conditions of mitochondrial impairment and oxidative stress. This review examines how mitochondrial quality-control (MQC) mechanisms-including biogenesis, dynamics, iron handling, and redox regulation-modulate ferroptotic sensitivity across female reproductive tissues. We highlight cell type-specific differences, ranging from ferroptosis-associated granulosa cell loss during follicular atresia to sublethal ferroptotic stress affecting oocyte competence and tightly restrained ferroptosis during decidualization and implantation. By integrating experimental and clinical evidence, we propose that mitochondrial regulation of ferroptosis acts as a context-dependent modulator of reproductive function rather than a uniform cell death pathway. Understanding this interplay provides new insight into ovarian aging, infertility, and uterine receptivity, with implications for reproductive medicine.
    Keywords:  Ferroptosis; infertility; mitochondria; ovary; oxidative stress; uterus
    DOI:  https://doi.org/10.1093/biolre/ioag132
  6. Nat Aging. 2026 Jul 02.
    Modulating IL-11-dependent matrix stiffness to delay ovarian aging.
    Meng Wu, Qingqing Zhu, Jiaqiang Xiong, Weicheng Tang, Dan Chen, Liru Xue, Yourong Feng, Yun Dai, Tong Wu, Chuqing Wu, Yican Guo, Simin Wei, Yibao Huang, Peizhe Zheng, Yuting Li, Yiqing Song, Ting Ding, Mingfu Wu, Zifu Li, Yueguang Rong, Wenwen Wang, Yan Li, Jun Dai, Shixuan Wang, Jinjin Zhang.
      Recent studies have highlighted the crucial role of mechanical properties in the ovarian microenvironment for ovarian function. However, the mechanisms that cause ovarian matrix stiffening during aging remain incompletely understood. Here we utilized atomic force microscopy (AFM) to demonstrate that human ovarian matrix stiffness increases with aging and in pathophysiological conditions, such as chemotherapy-induced premature ovarian insufficiency (POI), polycystic ovary syndrome (PCOS) and ovarian endometriosis. By integrating proteomic analysis of human ovarian tissue with transcriptomic profiling of human ovarian fibroblasts, we identified that IL-11, which is elevated in aging ovaries of mice, rats and humans, activates fibroblasts to secrete extracellular matrix (ECM), thereby increasing ovarian matrix stiffness. Genetic deletion of Il11ra1 in mice mitigated the increase in ovarian matrix stiffness and the decline in ovarian function associated with aging, chemotherapy-induced POI and PCOS. Single-nuclei RNA sequencing (snRNA-seq) revealed that blocking Il11ra1 reduces the proportion of activated fibroblasts. Furthermore, administration of siIl11 nanoparticles to aged mice and rats enhanced fertility and reduced ovarian matrix stiffness. Together, these findings highlight the pro-inflammatory factor IL-11 in regulating ovarian matrix stiffness. We propose that anti-IL-11 therapy represents a promising translational strategy for delaying ovarian aging.
    DOI:  https://doi.org/10.1038/s43587-026-01159-2
  7. bioRxiv. 2026 Jun 26. pii: 2026.06.22.732379. [Epub ahead of print]
    A Designed Ankyrin Repeat Protein (DARPin) Targeting EGFR Inhibits Ovulation and Enables a Novel Platform for Studying Ovarian Biology and Pathophysiology.
    Yubing Liu, Jiyang Zhang, Shichao Liu, Connie Mitra, Yue Liu, Hannah M VanBenschoten, Brittany Goods, Feng Chen, Shuo Xiao.
      Ovarian disorders, including anovulation, primary ovarian insufficiency (POI), and polyendocrine metabolic ovarian syndrome (PMOS), affect millions of reproductive-age women worldwide; however, mechanistic studies of ovarian biology and pathophysiology remain challenging because current experimental approaches often lack selectivity, tunability, or physiological relevance. Genetically modified animal models are labor-intensive and irreversible; small molecules frequently exhibit off-target effects; and conventional antibodies have limited tissue penetration and restricted temporal control. Designed ankyrin repeat proteins (DARPins) represent a highly modular protein engineering platform with advantages in specificity, size, stability, and extracellular targeting, but their utility in reproductive biology remains largely unexplored. Here, we used epidermal growth factor receptor (EGFR)-targeting DARPins as a proof-of-concept platform to interrogate ovarian signaling during ovulation. Screening of engineered anti-EGFR DARPins identified SX-006, a bispecific tetravalent construct with robust cross-species EGFR binding and potent biological activity. Using an ex vivo murine ovulation system, SX-006 inhibited follicle rupture in a dose-dependent manner with IC50 of 1.21 μM without overt cytotoxicity. Lower concentrations of SX-006 preferentially perturbed follicle rupture while largely preserving oocyte meiotic maturation and luteinization, suggesting differential sensitivity of ovulatory processes to extracellular EGFR blockade. Comparative transcriptomic analyses further revealed that extracellular EGFR blockade and small molecule-based intracellular EGFR kinase inhibition produce overlapping but also distinct transcriptional responses, supporting biologically distinct modes of ovulatory signaling pathway perturbation. Together, these findings establish DARPins as a selective, tunable, and physiologically relevant platform for studying ovarian signaling and provide proof-of-concept for extracellular receptor targeting in ovarian biology, infertility research, and non-hormonal contraceptive development.
    Summary sentence: An engineered EGFR-targeting DARPin selectively inhibits ovulation through extracellular receptor blockade and establishes a versatile platform for investigating ovarian signaling and reproductive disorders.
    DOI:  https://doi.org/10.64898/2026.06.22.732379
  8. Reproduction. 2026 Jul 02. pii: xaag079. [Epub ahead of print]
    Spatial Transcriptomics in Ovarian Biology Technologies, Computational Challenges, and Biological Insights.
    Ruixu Huang, Brittany Anne Goods.
      The ovary is a structurally complex organ whose function depends on precisely coordinated interactions among multiple cell types. Spatially resolved transcriptomics (ST) has emerged as a powerful complement to single-cell RNA sequencing (scRNA-seq), enabling gene expression profiling within intact tissue and preserving the spatial context that dissociation-based methods inherently lack. This review provides a comprehensive overview of the major ST platforms, including sequencing-based technologies (Visium, Visium HD, Stereo-seq, and GeoMx) and imaging-based technologies (Xenium, MERSCOPE, and CosMx), with a focus on their distinct technical features, resolution trade-offs, and suitability for ovarian research. We survey 40 published studies applying ST to ovarian biology, spanning atlases, ovarian aging, follicle development and ovulation, and ovarian cancer. We also discuss typical computational analyses as well as their challenges specific to ovary, including cell segmentation of morphologically diverse cell populations, deconvolution of mixed-cell capture spots in sequencing-based platforms, quality control, batch correction, and spatially aware downstream analyses encompassing trajectory inference, cell-cell interaction modeling, gene regulatory network reconstruction and more. Across these biological contexts, multi-modal integration, pairing ST with scRNA-seq, spatial proteomics, or chromatin accessibility profiling, has proven increasingly valuable for resolving the full molecular complexity of ovarian biology. Nevertheless, some challenges persist, and no single platform is universally optimal for all research questions. Thoughtful alignment between biological objectives, tissue scale, and platform capability will be critical for advancing ST from descriptive mapping toward mechanistic and clinically translatable discovery.
    Keywords:  Computational Biology; Ovary; Single-cell RNA Sequencing; Spatial Transcriptomics
    DOI:  https://doi.org/10.1093/reprod/xaag079
  9. Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2606092123
    Female reproductive dysfunction and transgenerational consequences following prolonged spaceflight exposure.
    Xiaoman Hong, Fereshteh Dalouchi, John C Prom, Michael E Ponte, Briana L Hockey, Jessica L Braun, Payton Nies, Avanelle Stoltz, V Praveen Chakravarthi, Molika Sinha, Sungshin Y Choi, April E Ronca, Joshua S Alwood, Val A Fajardo, E Matthew Morris, Stephanie Puukila, Lane K Christenson.
      Spaceflight presents unique gravitational, radiation, and isolation hazards for human exploration of the Moon, Mars, and beyond, yet its impact on the female reproductive system and successive generations has been largely unassessed. In the NASA Rodent Research 20 mission, we examined the impact of a 42-d spaceflight on the female reproductive axis including ovulatory capacity, implantation rate, and fecundity as well as behavioral, metabolic, and functional outcomes in F1 and F2 offspring. Females bred 5 d after return to Earth became pregnant but only exhibited a slight decline in fecundity compared to ground controls. In contrast, F1 offspring from spaceflight dams exhibited marked growth, functional, and behavioral differences compared to F1 offspring from control dams. Moreover, F1 female offspring from spaceflight dams exhibited decreased ovarian reserves as evidenced by reduced anti-Mullerian hormone levels early in life (21 d of age) and premature ovarian failure or an early loss in fertility, as indicated by reduced numbers of litters and total number of pups born to females over a 9-mo period. Strikingly, transgenerational metabolic and reproductive disturbances were also observed in F2 pups of spaceflight granddams, including persistent reductions in ovarian reserve, suggesting germline-level effects. Together these findings reveal significant short- and long-term impacts of spaceflight on the female reproductive system and on their offspring across generations, demonstrating biological transmission of reproductive vulnerability following maternal spaceflight exposure, and raising concerns for space travelers and colonization missions.
    Keywords:  fertility; microgravity; reproduction; spaceflight; transgenerational inheritance
    DOI:  https://doi.org/10.1073/pnas.2606092123
  10. Reproduction. 2026 Jul 01. pii: xaag081. [Epub ahead of print]
    Toll-like Receptor 4 Knockout Mice are Protected Against PMOS-like Pathogenesis.
    Kiara Wiggins, Zena Del Mundo, Julio Ayala Angulo, Nandini Naidu, Angelina Saba, Lily Zhou, Christopher Garcia, Christy M Nguyen, Naveena Ujagar, Jamie-Jean De La Torre, Gabriela De Robles, Angie Rivera, Davina Trinh, Roberto Tinoco, Alexander S Kauffman, Varykina G Thackray, Anshu Agrawal, Marcus Seldin, Gabriela Pacheco-Sanchez, Dequina A Nicholas.
      Polyendocrine metabolic ovarian syndrome (PMOS), formerly termed polycystic ovary syndrome (PCOS), is a reproductive disorder with heterogeneous symptoms and severity. Despite extensive research documenting chronic immune dysfunction as a hallmark of PMOS, the specific mechanisms of immune activation remain poorly understood. Emerging evidence suggests that gut-derived bacterial endotoxins, particularly lipopolysaccharide (LPS), can breach intestinal barriers and trigger systemic inflammation via Toll-like receptor 4 (TLR4). This study examined the role of TLR4 in PMOS-like pathology using a letrozole (LET)-induced mouse model. In LET-treated wild-type female mice, serum LPS and its carrier protein LBP were elevated compared to LET-treated TLR4-/- mice. Additionally, TLR4 deficiency attenuated multiple PMOS-like features, including elevated luteinizing hormone, anovulation, and metabolic dysfunction. LET-treated TLR4-/- mice also preserved estrous cycling and fertility, maintained gut barrier integrity, and reduced inflammatory markers. These findings support TLR4 as an important contributor to multiple features of PMOS-like pathology. This novel work highlights TLR4-mediated inflammation as a potential target for anti-inflammatory treatments in women with PMOS.
    Keywords:  Inflammation; Metabolic; PCOS; PMOS; Reproduction; TLR4
    DOI:  https://doi.org/10.1093/reprod/xaag081
  11. Open Biol. 2026 Jul 01. pii: 260006. [Epub ahead of print]16(7):
    Understanding GnRH: local systems, signalling mechanisms and implications in female health.
    Lily Tosh, Kirsty Tinto, Margaret Cunningham, Paul Mulheran, Valerie Ferro.
      Gonadotropin-releasing hormone (GnRH) is a peptide hormone forming a central component of the hypothalamic-pituitary-gonadal axis and is critical for controlling reproductive functions. Dysregulated GnRH is implicated in many steroid hormone-dependent diseases, and its receptor, GnRHR, is an attractive and clinically exploited therapeutic target. Mounting evidence suggests that beyond the hypothalamus and pituitary, GnRH and GnRHR are expressed in reproductive and non-reproductive, healthy and malignant peripheral tissues, where they act in an autocrine and paracrine manner. This review provides an updated overview of GnRH and GnRHR signalling with a focus on extrapituitary autocrine and paracrine roles in female reproductive health. We examine the molecular and cellular mechanisms of extrapituitary GnRHR signalling, including G-protein coupling profiles, and alternative cell-specific mechanisms that differ from pituitary signalling. We highlight recent data surrounding the (patho) physiological functions of local GnRH systems, including in the endometrium, ovary, placenta and breast, and their implications for hormone-dependent gynaecological conditions and cancers. Finally, we consider implications of peripheral GnRH/GnRHR systems for therapeutic innovation, including avenues for targeted or biased GnRH-based therapeutics, GnRH/GnRHR-mediated 'off target' effects of GnRH analogues, and explore future translational avenues for the treatment of both hormone-dependent and hormone-refractory diseases.
    Keywords:  GPCR-signal transduction; GnRH; GnRH receptor; HPG axis; cell signalling; extrapituitary; female health; reproduction
    DOI:  https://doi.org/10.1098/rsob.260006
  12. Sci Adv. 2026 Jul 03. 12(27): eaed9156
    Illuminating aging with multimodal optical metabolic imaging.
    Yajuan Li, Erick Alvarado, Zhi Li, Rohan Shrestha, Jorge Villazon, Lingyan Shi.
      Aging is intimately entangled with the reprogramming of metabolic pathways that coordinate energy production, biosynthesis, and molecular turnover. However, visualizing and understanding these metabolic underpinnings within their spatial and temporal contexts remains a major challenge. Metabolic imaging has emerged as a transformative approach that enables spatially resolved visualization of metabolic dynamics both at the molecular or cellular and organismal levels. In this review, we summarize recent advances and applications of metabolic imaging in probing aging biology, with particular emphasis on multimodal nonlinear optical imaging techniques and their applications across diverse aging models. Optical metabolic imaging provides unique insights into the mechanisms of aging by capturing metabolic alterations that span from organelle-level interactions to tissue-scale remodeling. Optical metabolic imaging enables the label-free detection of early metabolic shifts in vivo, representing an emerging frontier in aging research. Looking ahead, optical metabolic imaging holds great promise as a practical and powerful tool for clinical translation, advancing precision medicine and enhancing the diagnosis, monitoring, and evaluation of aging processes to promote human health span and longevity.
    DOI:  https://doi.org/10.1126/sciadv.aed9156
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