Key Takeaways & Executive Findings
- •• Isorhamnetin preconditioning enhances MSC-derived exosomes' therapeutic efficacy against chemotherapy-induced premature ovarian failure. • ISO-MSC-Exos suppress ferroptosis by downregulating Alox15 and Tf, reducing lipid peroxidation and iron uptake. • ISO-MSC-Exos restore ovarian function, hormone levels, and fertility more effectively than unmodified MSC-Exos. • This study provides a novel cell-free therapeutic strategy for POF, potentially applicable to other ferroptosis-related diseases.
Abstract
Background Chemotherapy-induced premature ovarian failure (POF) is a major cause of infertility, with limited treatment options. Mesenchymal stem cell-derived exosomes (MSC-Exos) have therapeutic potential. This study investigated whether preconditioning MSCs with the antioxidant flavonoid isorhamnetin (ISO) enhances the efficacy of their exosomes (ISO-MSC-Exos) against POF. Methods A cyclophosphamide-induced POF rat model was established, and the role of the ferroptosis inhibitor ferrostatin-1 was evaluated. MSC-Exos and ISO-MSC-Exos were isolated by ultracentrifugation and administered via tail vein injection. Ovarian recovery was assessed by monitoring the oestrous cycle, serum hormone levels, and histological findings. Lipid peroxidation and iron metabolism were evaluated by quantifying malondialdehyde, glutathione, iron deposition, and mitochondrial ultrastructure. Immunohistochemistry was used to assess the expression levels of GPX4, ACSL4, and FTH1. Proteomic analyses were performed to explore the underlying mechanisms. Results Ferroptosis plays a pivotal role in the cyclophosphamide-induced POF rat model. Both exosome therapies improved ovarian function and suppressed ferroptosis, with ISO-MSC-Exos showing superior efficacy. ISO-MSC-Exos significantly restored hormone levels, ameliorated oestrous cycle disorders, reduced follicular atresia, and enhanced fertility. Furthermore, ISO-MSC-Exos more effectively elevated glutathione levels, reduced malondialdehyde and Fe2⁺ levels, and reversed the abnormal expression of ferroptosis-related proteins GPX4, ACSL4, and FTH1. Proteomic analysis suggested that ISO-MSC-Exos effectively inhibit ferroptosis by downregulating Alox15 and Tf, thereby reducing lipid peroxidation substrates and cellular iron uptake. This finding represents a potential molecular mechanism underlying their superior efficacy compared with that of MSC-Exos. Conclusions ISO-MSC-Exos showed superior efficacy compared with MSC-Exos in restoring ovarian function and inhibiting ferroptosis, suggesting that ISO pretreatment enhances the therapeutic effect of MSC-Exos in the POF
1. Introduction
Premature ovarian failure (POF) refers to the premature decline of ovarian function in women before the age of 40. Clinically, it is characterized by infrequent menstruation, amenorrhea, and reduced fertility. Endocrine manifestations typically include elevated follicle-stimulating hormone (FSH) levels, reduced estrogen (E2), and decreased anti-Müllerian hormone (AMH), which are key indicators of ovarian reserve function [1, 2]. The prevalence of POF among women under 40 is approximately 1% [3], although its precise etiology and pathogenesis remain unclear. Contributing factors include genetic predisposition, autoimmune responses, iatrogenic causes, and environmental influences [4]. In recent years, with the trend toward earlier onset of cancer, iatrogenic factors such as chemotherapy and radiotherapy have emerged as major risk factors for POF in young women undergoing cancer treatment [5]. Hormone replacement therapy remains the primary clinical approach; however, long-term use is associated with increased risks of breast and ovarian cancers, as well as thrombosis [6, 7]. Moreover, it does not effectively restore reproductive function. Therefore, there is an urgent need for safer and more effective therapeutic strategies.
In recent years, mesenchymal stem cells (MSCs) have shown significant potential as multipotent stem cells for the treatment of tissue damage [8]. MSCs possess strong paracrine effects, immunomodulatory properties, and multipotent differentiation capacity [9]. However, compared with MSCs themselves, exosomes secreted by MSCs exhibit greater stability, superior biocompatibility, and lower immunogenicity in vivo [10]. Consequently, MSC-derived exosomes (MSC-Exos) hold considerable promise as emerging cell-free therapeutic agents. Recent studies have shown that MSC-Exos can improve ovarian function in animal models of POF by reducing oxidative stress, inhibiting apoptosis, and exerting antifibrotic effects [11, 12]. Nevertheless, the therapeutic efficacy of MSC-Exos remains suboptimal, necessitating strategies to enhance their potency.
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Qiang Zhang, Jinyu Yu, Yan Zheng, Jinlan Jiang, Lianwen Zheng (2026). Isorhamnetin-preconditioned MSC-derived exosomes restore ovarian function by inhibiting ferroptosis in chemotherapy-induced POF. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-026-04989-4
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Frequently Asked Questions
What is premature ovarian failure (POF)?
Premature ovarian failure (POF) is the decline of ovarian function in women before age 40, characterized by irregular menstruation, amenorrhea, and reduced fertility, often with elevated FSH and low estrogen levels.
How do MSC-derived exosomes help in POF?
MSC-derived exosomes (MSC-Exos) can improve ovarian function in POF models by reducing oxidative stress, inhibiting apoptosis, and exerting antifibrotic effects, as demonstrated in animal studies.
What is the role of isorhamnetin in this study?
Isorhamnetin (ISO) is an antioxidant flavonoid used to precondition MSCs, enhancing the therapeutic efficacy of their exosomes (ISO-MSC-Exos) against POF by further suppressing ferroptosis.
What is ferroptosis and how does it relate to POF?
Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation. This study shows that ferroptosis plays a pivotal role in chemotherapy-induced POF, and inhibiting it with ISO-MSC-Exos restores ovarian function.
What are the key molecular mechanisms of ISO-MSC-Exos?
ISO-MSC-Exos inhibit ferroptosis by downregulating Alox15 and Tf, reducing lipid peroxidation substrates and cellular iron uptake, thereby protecting ovarian cells and restoring function.
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