bims-ovagas 2026-04-19 papers

Biomed Pharmacother. 2026 Apr 15. pii: S0753-3322(26)00349-5. [Epub ahead of print]199 119316

Ovarian radiation injury and protection: Mechanisms, delivery-enabled interventions, and future directions.

Yao Liu, Shourong Wang, Chunrun Yang, Guoyun Wang.

Incidental ovarian irradiation during pelvic radiotherapy or total-body irradiation leads to irreversible endocrine dysfunction, premature ovarian insufficiency, and infertility in young women with cancer. Current clinical strategies-ovarian transposition, shielding, and organ-at-risk dose constraints-provide only partial protection and offer limited control over temporal exposure or spatial confinement. These limitations underscore the need for delivery-enabled radioprotective systems capable of targeting the ovary with precision, synchronizing protection with radiation fractions, and minimizing tumor co-protection.This review integrates the mechanistic foundations of ovarian radiosensitivity with emerging opportunities in drug delivery and biomaterials engineering. We first summarize key biological pathways-including DSB-CHK2/TAp63-mediated oocyte apoptosis, ferroptosis-associated lipid peroxidation (GPX4 loss, 4-HNE accumulation), mitochondrial injury, and microvascular-stromal remodeling-that collectively define the ovarian vulnerability to ionizing radiation and reveal discrete physicochemical intervention windows. Building on this foundation, we evaluate a spectrum of next-generation delivery platforms with direct relevance to ovarian radioprotection: antibody-drug conjugates for ovary-targeted intracellular deposition; lipid nanoparticle-mediated siRNA for transient pathway modulation; ultrasound- or magnetically actuated micro/nanomotors for active tissue penetration and precision positioning; and injectable biodegradable hydrogels for localized, fraction-matched release.We also highlight the emerging "estrogen-anti-ferroptosis axis" as a hypothesis-generating pathway that may synergize with material-enabled strategies to reduce early oxidative and lipid-peroxidative injury. Together, these insights outline a translational roadmap for integrating targeting, controlled release, and bioresponsive materials into radiotherapy workflows, offering new directions for precise, organ-specific protection without compromising oncologic control.

Keywords: Ferroptosis; Fertility Preservation; Ovarian Radiation Injury; Radioprotector; Targeted Delivery

DOI: https://doi.org/10.1016/j.biopha.2026.119316

Nat Commun. 2026 Apr 13.

Intraovarian injection of securinine stimulates the growth of small ovarian follicles by reducing stromal suppression.

Yu Zhao, Dongteng Liu, Zexiong Lin, Shuzi Deng, Xudong Zhao, Yiting Sun, Yihui Zhang, Qiong Zhang, Jingkai Gu, Yuan Xiao, Tianren Wang, Haonan Lu, Jing Zhao, Karen K L Chan, Yu Li, William S B Yeung, Kui Liu.

The lack of hormone-responsive follicles is a major challenge in treating infertility/subfertility in women with premature ovarian insufficiency or diminished ovarian reserve. In this study, we demonstrate that securinine, a neurological drug, can be repurposed to promote small follicle growth. In aged mice, intraovarian injection of securinine significantly enhances follicular development and improves fertility, yielding healthy offspring. Mechanistically, single-cell RNA sequencing reveals that securinine promotes follicular development by alleviating the negative regulation from the stromal extracellular matrix on granulosa cells. Furthermore, intraovarian injection of securinine in aged cynomolgus macaques effectively stimulates the development of small follicles into large antral follicles. Our findings highlight securinine as a promising candidate for ultrasound-guided ovarian injection for treating infertility/subfertility in women with premature ovarian insufficiency, diminished ovarian reserve, or advanced maternal age. As a small molecule drug, intraovarian securinine injection offers clinical advantages that avoid complex preparation procedures required for platelet-rich plasma or stem cell-based therapies.

DOI: https://doi.org/10.1038/s41467-026-71691-7

Endocrinology. 2026 Apr 16. pii: bqag042. [Epub ahead of print]

A protocol for physiologic LH surge induction in gonad intact female mice.

Mauro S B Silva, Rajae Talbi, Encarnación Torres, Samuel Zdon, Sidney A Pereira, George A Stamatiades, Isabel Lopez, Rona S Carroll, Víctor M Navarro.

The preovulatory luteinizing hormone (LH) surge is a defining neuroendocrine event that triggers ovulation through estradiol (E2)-dependent positive feedback on gonadotropin-releasing hormone (GnRH) secretion. Mechanistic studies of this process have relied predominantly on ovariectomized rodents supplemented with exogenous hormones, a paradigm that disrupts ovarian function and limits physiological and translational relevance. Here, we establish a robust and reproducible model of LH surge induction in intact female mice that preserves the hypothalamic-pituitary-gonadal axis. We show that a single low-dose injection of estradiol benzoate (EB; 0.5 µg) administered during diestrus reliably induces a temporally synchronized LH surge in most intact females, whereas EB treatment during proestrus or estrus is ineffective. EB-induced LH surges were accompanied by a significant rise in circulating progesterone, confirming engagement of ovarian luteinizing pathways. The LH surge occurrence was independent of proestrus detection by vaginal cytology, accentuating the limited predictive value of cytology in mice. At the neuroendocrine level, EB treatment markedly increased cFOS expression in GnRH neurons across key preoptic regions and modestly activated kisspeptin neurons in the rostral periventricular area of the third ventricle, consistent with activation of E2-positive feedback circuitry. In contrast, arcuate kisspeptin neurons remained inactive, supporting their role in negative feedback. Together, these findings define a physiologically relevant, intact mouse model for studying E2-induced LH surges that maintains endogenous ovarian signaling.

DOI: https://doi.org/10.1210/endocr/bqag042

bioRxiv. 2026 Apr 09. pii: 2026.04.06.716785. [Epub ahead of print]

3D imaging of the pregnant uterus reveals an extensively invasive mouse placenta and early CXCL12-CXCR4 requirement.

James B Zwierzynski, Mira N Moufarrej, Kristy Red-Horse.

Successful pregnancy requires exquisite balance: the placenta must invade just enough to access maternal blood but not so deep it remains attached at birth. Disrupting this balance causes life-threatening pregnancy complications, for which treatments remain limited. Animal models are desperately needed to discover mechanisms underlying balanced uteroplacental development and how pregnancy complications arise, but this is hampered by the view that mouse placentation lacks human characteristics such as extensive trophoblast invasion and targeting of uterine spiral arteries. Here, we utilize 3D imaging, mouse genetics, and pharmacological perturbations to demonstrate that: (1) The mouse placenta invades more extensively than previously recognized with most spiral arteries heavily enveloped by fetal trophoblasts, (2) This process is disrupted without CXCL12-CXCR4 signaling specifically during early pregnancy, and (3) Disrupting early uteroplacental development ultimately results in excessively deep trophoblast invasion, closely mimicking the pregnancy complication placenta accreta. Mechanistically, uterine epithelium, stroma, and arteries activate CXCR4 signaling in early pregnancy, and inhibition causes decidualization failure, followed by dissolution of spiral artery development. Trophoblasts consequently migrate deep into uterine muscle and its arteries, reproducing hallmarks of human accreta. Thus, with 3D imaging, the mouse more effectively models human uteroplacental development and defines an early etiological window for intervention.

DOI: https://doi.org/10.64898/2026.04.06.716785

Biol Reprod. 2026 Apr 08. pii: ioag073. [Epub ahead of print]

The Effects of Iodoacetic Acid on Oxidative Stress Markers in the Mouse Ovary†.

Audrey L Fields, Andressa Varella Gonsioroski, Ramsés Santacruz Márquez, Mary J Laws, Jodi A Flaws.

The incorporation of water disinfectants into the main water supply has significantly decreased the incidence of waterborne diseases. However, the interaction between disinfectants and organic material generates water disinfection byproducts (DBPs) such as iodoacetic acid (IAA). IAA is an ovarian toxicant, but little is known about its mechanisms of toxicity. Thus, we tested the hypothesis that IAA exposure causes ovarian toxicity through oxidative stress pathways. Adult CD-1 mice were dosed with vehicle control (reverse osmosis water) or IAA (2.7- 2,695.7 μM) for 35 days. Then, whole ovaries or isolated antral follicles were collected for measurement of expression of several enzymes that regulate oxidative stress (Gpx1, Gpx2, Gsr, Gss, Gsta1, Gstm1, Gsto1, Gstp1 Gstt1, Sod1, Sod2, and Cat). In other experiments, antral follicles were cultured with vehicle control ± the antioxidant Trolox or IAA (2-15 μM) ± the antioxidant Trolox for 96 hours and follicle growth was measured every 24 hours. Media were collected for estradiol measurements. IAA decreased Cat, Sod1, Gss, Gsta1, Gstp1, and Gstt1 and increased Gstm1 expression in whole ovaries compared to control in vivo. IAA decreased Sod2 and Gpx2 and increased Gstp1 expression in antral follicles compared to control in vivo. IAA increased Gpx1 and Gsto1 expression in antral follicles compared to control in vitro. IAA inhibited follicle growth and reduced estradiol levels, whereas Trolox rescued follicles from IAA-induced inhibition of follicle growth and estrogen levels in vitro. Collectively, these data indicate that IAA exposure causes ovarian toxicity by altering oxidative stress pathways in the mouse ovary.

Keywords: Iodoacetic Acid; Ovary; Oxidative Stress; Toxicant; Water Disinfectant Byproduct

DOI: https://doi.org/10.1093/biolre/ioag073