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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Alpha-Lipoic Acid and Saxagliptin Attenuate Ferroptosis-Related Ovarian Injury and Modulate FGF21/NOX4–NRF2/HO-1 Signaling in Letrozole-Induced Polycystic Ovary Syndrome

  • Eman H. Yousef1
  • Mona H. Zohny2
  • Ebtsam S. Abdel-lah3,4
  • Mostafa E. Metawee5,6
  • Hader I. Sakr7,8
  • Mohamed M. Salama2
8 affiliations
  1. 1Department of Pharmacology and Biochemistry (Biochemistry), Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt
  2. 2Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
  3. 3Department of Pharmacology, Faculty of Veterinary Medicine, Assiut University, Assiut 71526, Egypt
  4. 4Department of Pharmacology, School of Veterinary Medicine, Badr University in Assiut (BUA), Naser City 11829, Egypt
  5. 5Department of Histology, Faculty of Medicine (Boys), Al-Azhar University, Cairo 11884, Egypt
  6. 6Department of Histology, General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia
  7. 7Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo 12613, Egypt
  8. 8Department of Medical Physiology, General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia
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Abstract

Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder characterized by ovarian dysfunction, hormonal imbalance, and emerging ferroptosis-related abnormalities. This study investigated the effects of alpha-lipoic acid (ALA), saxagliptin (Saxa), and their combination in a letrozole-induced PCOS model, with focus on the ovarian FGF21/NOX4–NRF2/HO-1 and ferroptosis-related pathways. PCOS was induced in female rats by oral letrozole administration for 21 days. Rats were allocated into control, PCOS, ALA, Saxa, and ALA/Saxa groups, followed by 14 days of treatment. Body weight, ovarian index, ovarian histopathology, reproductive hormones, oxidative stress markers, ovarian FGF21 and NOX4 expression, NRF2/HO-1 signaling, and ferroptosis-related markers, including Fe+2, GPX4, and SLC7A11, were assessed. Letrozole induced weight gain, ovarian hypertrophy, follicular disruption, endocrine imbalance, and ferroptosis-related alterations, marked by increased ROS, MDA, Fe2+, and NOX4, alongside reduced FGF21, NRF2/HO-1, GPX4, and SLC7A11. ALA or Saxa attenuated these alterations, whereas ALA/Saxa produced greater improvements in ovarian morphology, hormonal status, redox homeostasis, and ferroptosis-related markers. These effects were associated with FGF21 upregulation, NOX4 suppression, enhanced NRF2/HO-1 signaling, and preservation of GPX4 and SLC7A11. In conclusion, ALA/Saxa therapy markedly ameliorated letrozole-induced PCOS in rats, accompanied by restoration of ovarian FGF21/NOX4 homeostasis, associated with enhancement of NRF2/HO-1 antioxidant responses, and attenuation of ferroptosis-related alterations.

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Cite

BibTeXRIS
BibTeX
@article{yousef2026alphalipoic,
  title = {{Alpha-Lipoic Acid and Saxagliptin Attenuate Ferroptosis-Related Ovarian Injury and Modulate FGF21/NOX4–NRF2/HO-1 Signaling in Letrozole-Induced Polycystic Ovary Syndrome}},
  author = {Eman H. Yousef and Mona H. Zohny and Ebtsam S. Abdel-lah and Mostafa E. Metawee and Hader I. Sakr and Mohamed M. Salama},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219779},
  url = {https://www.mdpi.com/1422-0067/27/21/9779},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Alpha-Lipoic Acid and Saxagliptin Attenuate Ferroptosis-Related Ovarian Injury and Modulate FGF21/NOX4–NRF2/HO-1 Signaling in Letrozole-Induced Polycystic Ovary Syndrome
AU  - Eman H. Yousef
AU  - Mona H. Zohny
AU  - Ebtsam S. Abdel-lah
AU  - Mostafa E. Metawee
AU  - Hader I. Sakr
AU  - Mohamed M. Salama
PY  - 2026
DA  - 2026/10/30
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219779
UR  - https://www.mdpi.com/1422-0067/27/21/9779
AB  - Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder characterized by ovarian dysfunction, hormonal imbalance, and emerging ferroptosis-related abnormalities. This study investigated the effects of alpha-lipoic acid (ALA), saxagliptin (Saxa), and their combination in a letrozole-induced PCOS model, with focus on the ovarian FGF21/NOX4–NRF2/HO-1 and ferroptosis-related pathways. PCOS was induced in female rats by oral letrozole administration for 21 days. Rats were allocated into control, PCOS, ALA, Saxa, and ALA/Saxa groups, followed by 14 days of treatment. Body weight, ovarian index, ovarian histopathology, reproductive hormones, oxidative stress markers, ovarian FGF21 and NOX4 expression, NRF2/HO-1 signaling, and ferroptosis-related markers, including Fe+2, GPX4, and SLC7A11, were assessed. Letrozole induced weight gain, ovarian hypertrophy, follicular disruption, endocrine imbalance, and ferroptosis-related alterations, marked by increased ROS, MDA, Fe2+, and NOX4, alongside reduced FGF21, NRF2/HO-1, GPX4, and SLC7A11. ALA or Saxa attenuated these alterations, whereas ALA/Saxa produced greater improvements in ovarian morphology, hormonal status, redox homeostasis, and ferroptosis-related markers. These effects were associated with FGF21 upregulation, NOX4 suppression, enhanced NRF2/HO-1 signaling, and preservation of GPX4 and SLC7A11. In conclusion, ALA/Saxa therapy markedly ameliorated letrozole-induced PCOS in rats, accompanied by restoration of ovarian FGF21/NOX4 homeostasis, associated with enhancement of NRF2/HO-1 antioxidant responses, and attenuation of ferroptosis-related alterations.
SN  - 1422-0067
ER  -