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Background <p>Ovarian tissue is highly sensitive to ionizing radiation; even low-dose exposure can lead to premature ovarian failure and infertility. However, the molecular mechanisms underlying radiation-induced ovarian damage and potential protective interventions remain incompletely defined.</p> Methods <p>Using a rat model of abdominal irradiation, we investigated whether sphingosine-1-phosphate (S1P) protects against radiation-induced ovarian injury by modulating ferroptosis. Rats were pretreated with S1P, with or without the glutamate-cysteine ligase catalytic subunit (GCLC) inhibitor L-buthionine sulfoximine (BSO) or the ferroptosis inhibitor ferrostatin-1 (Fer-1). Ovarian histopathology, follicle counts, serum hormone levels, inflammatory and oxidative stress markers, and ferroptosis-related proteins were analyzed.</p> Results <p>S1P treatment significantly alleviated radiation-induced structural and functional ovarian damage by preserving ovarian architecture, increasing follicle number (notably primordial follicles), normalizing serum hormone levels, and reducing inflammatory cytokines. Mechanistically, S1P mitigated mitochondrial injury and oxidative stress by decreasing iron accumulation, lipid peroxidation, and reactive oxygen species (ROS) levels, while restoring glutathione (GSH), superoxide dismutase (SOD), and mitochondrial membrane potential. Mechanistically, S1P enhanced the expression of GCLC and glutathione peroxidase 4 (GPX4), suppressed transferrin receptor 1 (TfR1) expression, and transiently activated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Pharmacological inhibition of GCLC by BSO abolished these protective effects, confirming the essential role of the Nrf2–GCLC–GPX4 axis in regulating ferroptosis and redox balance.</p> Conclusions <p>S1P protects against radiation-induced ovarian injury by suppressing ferroptosis through upregulation of GCLC and GPX4 downstream of Nrf2 activation. These findings identify S1P as a potential therapeutic agent for preserving ovarian function during radiotherapy and highlight the GCLC-GSH-GPX4 pathway as a critical target for ovarian radioprotection.</p>

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Sphingosine-1-phosphate mitigates radiation-induced ovarian injury in rats by suppressing ferroptosis via activating the Nrf2-GCLC-GPX4 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Jiahui Zhao,
  • Fengmei Cui,
  • Da Li,
  • Mei Wang,
  • Lisha Tang,
  • Hong Zhang

摘要

Background

Ovarian tissue is highly sensitive to ionizing radiation; even low-dose exposure can lead to premature ovarian failure and infertility. However, the molecular mechanisms underlying radiation-induced ovarian damage and potential protective interventions remain incompletely defined.

Methods

Using a rat model of abdominal irradiation, we investigated whether sphingosine-1-phosphate (S1P) protects against radiation-induced ovarian injury by modulating ferroptosis. Rats were pretreated with S1P, with or without the glutamate-cysteine ligase catalytic subunit (GCLC) inhibitor L-buthionine sulfoximine (BSO) or the ferroptosis inhibitor ferrostatin-1 (Fer-1). Ovarian histopathology, follicle counts, serum hormone levels, inflammatory and oxidative stress markers, and ferroptosis-related proteins were analyzed.

Results

S1P treatment significantly alleviated radiation-induced structural and functional ovarian damage by preserving ovarian architecture, increasing follicle number (notably primordial follicles), normalizing serum hormone levels, and reducing inflammatory cytokines. Mechanistically, S1P mitigated mitochondrial injury and oxidative stress by decreasing iron accumulation, lipid peroxidation, and reactive oxygen species (ROS) levels, while restoring glutathione (GSH), superoxide dismutase (SOD), and mitochondrial membrane potential. Mechanistically, S1P enhanced the expression of GCLC and glutathione peroxidase 4 (GPX4), suppressed transferrin receptor 1 (TfR1) expression, and transiently activated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Pharmacological inhibition of GCLC by BSO abolished these protective effects, confirming the essential role of the Nrf2–GCLC–GPX4 axis in regulating ferroptosis and redox balance.

Conclusions

S1P protects against radiation-induced ovarian injury by suppressing ferroptosis through upregulation of GCLC and GPX4 downstream of Nrf2 activation. These findings identify S1P as a potential therapeutic agent for preserving ovarian function during radiotherapy and highlight the GCLC-GSH-GPX4 pathway as a critical target for ovarian radioprotection.