ArticleInternational journal of molecular sciences2022
Aberrant Transferrin and Ferritin Upregulation Elicits Iron Accumulation and Oxidative Inflammaging Causing Ferroptosis and Undermines Estradiol Biosynthesis in Aging Rat Ovaries by Upregulating NF-Κb-Activated Inducible Nitric Oxide Synthase: First Demonstration of an Intricate Mechanism.
Article in International journal of molecular sciences, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 43 citations in OpenAlex.
- PGE2 regulates ferroptosis and osteogenesis of MC3T3-E1 cells via NOS2.Scientific reports · 2026Article
- Mitochondria and polycystic ovary syndrome: The role of ferroptosis, inflammasomes, and endoplasmic reticulum stress.International journal of biological sciences · 2026Review
- Analyzing the association between ferritin levels and ICP using machine learning algorithms: a retrospective case-control study.Frontiers in medicine · 2026Article
- The inflammatory clock: how cGAS-STING ticks in the aging ovary.Frontiers in cell and developmental biology · 2026Review
- Ferroptosis-neuroinflammation interplay: mechanistic pathways and therapeutic opportunities in central nervous system disorders.Frontiers in aging neuroscience · 2026Review
- Oviductus Ranae alleviates D-galactose-induced ovarian aging by inhibiting ferroptosis and regulating the GPX4/ACSL4 pathway.Journal of ovarian research · 2025Article
- Vortioxetine protects against methotrexate-induced ovarian toxicity through anti-inflammatory, antioxidant and antiapoptotic pathways: a multi-marker immunohistochemical study.Journal of molecular histology · 2025Article
- Article
- The Mechanism of Ferroptosis Regulating Granulosa Cell Apoptosis and Oxidative Stress Through the NF-κB/PTGS2 Axis in Porcine Atretic Follicles.Antioxidants (Basel, Switzerland) · 2025Article
- Targeting Ferroptosis to Eliminate Senescent Cells: Mechanisms and Therapeutic Potential.Aging and disease · 2025Review
- Non-coding RNA-mediated granulosa cell dysfunction during ovarian aging: From mechanisms to potential interventions.Non-coding RNA research · 2025Review
- Reactive oxygen and nitrogen species: multifaceted regulators of ovarian activity†.Biology of reproduction · 2025Review
- Overview of Nrf2 as a target in ovary and ovarian dysfunctions focusing on its antioxidant properties.Journal of ovarian research · 2025Review
- Targeting programmed cell death with natural products: a potential therapeutic strategy for diminished ovarian reserve and fertility preservation.Frontiers in pharmacology · 2025Review
- Iron status and sarcopenia-related traits: a bi-directional Mendelian randomization study.Scientific reports · 2024Article
- Glutaredoxin-1 modulates the NF-κB signaling pathway to activate inducible nitric oxide synthase in experimental necrotizing enterocolitis.Molecular therapy. Methods & clinical development · 2024Article
- Moderate mechanical stress suppresses chondrocyte ferroptosis in osteoarthritis by regulating NF-κB p65/GPX4 signaling pathway.Scientific reports · 2024Article
- Ovaries of estrogen receptor 1-deficient mice show iron overload and signs of aging.Frontiers in endocrinology · 2024Article
- N-Stearoylethanolamine Exerts Cardioprotective Effects in Old Rats.Current aging science · 2024Article
- Oxidative stress and inflammatory markers in ovarian follicular fluid of women with diminished ovarian reserve during in vitro fertilization.Journal of ovarian research · 2023Article
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Authors and funding
10 authors at 3 institutions in 3 countries.
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Abstract
We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile ferrous iron and total iron levels escalated with age in rats. Oxidative stress markers, such as nitrite/nitrate, 3-nitrotyrosine, and 4-hydroxy-2-nonenal, accumulated in the aging ovaries due to an aberrant upregulation of the ovarian transferrin, ferritin light/heavy chains, and iron regulatory protein 2(IRP2)-mediated transferrin receptor 1 (TfR1). Ferritin inhibited estradiol biosynthesis in ovarian granulosa cells in vitro via the upregulation of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p65/p50-induced oxidative and inflammatory factor inducible nitric oxide synthase (iNOS). An in vivo study demonstrated how the age-associated activation of NF-κB induced the upregulation of iNOS and the tumor necrosis factor α (TNFα). The downregulation of the keap1-mediated nuclear factor erythroid 2-related factor 2 (Nrf2), that induced a decrease in glutathione peroxidase 4 (GPX4), was observed. The aberrant transferrin and ferritin upregulation triggered an iron accumulation via the upregulation of an IRP2-induced TfR1. This culminates in NF-κB-iNOS-mediated ovarian oxi-inflamm-aging and serum estradiol decrement in naturally aging rats. The iron accumulation and the effect on ferroptosis-related proteins including the GPX4, TfR1, Nrf2, Keap1, and ferritin heavy chain, as in testicular ferroptosis, indicated the triggering of ferroptosis. In young rats, an intraovarian injection of an adenovirus, which expressed iron regulatory proteins, upregulated the ovarian NF-κB/iNOS and downregulated the GPX4. These novel findings have contributed to a prompt translational research on the ovarian aging-associated iron metabolism and aging-associated ovarian diseases.
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