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Antioxidants
Volume 14
Issue 9
10.3390/antiox14091058
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Ferrostatin-1 Prevents Salivary Gland Dysfunction in an Ovariectomized Rat Model by Suppressing Mitophagy-Driven Ferroptosis

by
Gi Cheol Park
1,
Soo-Young Bang
2,
Ji Min Kim
2,
Sung-Chan Shin
2,
Yong-il Cheon
2,
Hanaro Park
1,
Sunghwan Suh
3,
Jung Hwan Cho
3,
Eui-Suk Sung
4,
Minhyung Lee
4,
Jin-Choon Lee
4 and
Byung-Joo Lee
5,*
1
Department of Otolaryngology—Head and Neck Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Republic of Korea
2
Department of Otorhinolaryngology—Head and Neck Surgery, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
3
Divisions of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Republic of Korea
4
Department of Otorhinolaryngology—Head and Neck Surgery, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Yangsan Hospital, Yangsan 50613, Republic of Korea
5
Department of Otorhinolaryngology-Head and Neck Surgery, Good Gang-An Hospital, Busan 48265, Republic of Korea
*
Author to whom correspondence should be addressed.
Antioxidants 2025, 14(9), 1058; https://doi.org/10.3390/antiox14091058 (registering DOI)
Submission received: 23 June 2025 / Revised: 8 August 2025 / Accepted: 19 August 2025 / Published: 28 August 2025
(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)
Versions Notes

Abstract

Salivary gland dysfunction is a common but underexplored complication of menopause that contributes to oral dryness, dysphagia, and increased risk of infection. Although ferroptosis, a form of regulated necrotic cell death driven by iron-dependent lipid peroxidation, has recently been implicated in postmenopausal tissue degeneration, its regulatory mechanisms in salivary glands remain unclear. In this study, we investigated the roles of mitochondrial dysfunction and mitophagy in driving ferroptosis-induced salivary gland injury in an ovariectomized (OVX) rat model of estrogen deficiency. OVX rats exhibited elevated markers of oxidative stress, lipid accumulation, and iron overload, and suppression of GPX4 activity in the salivary glands, consistent with ferroptotic activation. These changes were accompanied by impaired mitochondrial dynamics (MFN1 and OPA1), decreased expression of mitochondrial antioxidant regulators (PGC-1α, SOD, and catalase), and upregulation of mitophagy-related genes (PINK1, ULK1, Rab9, and LC3B), as well as LAMP, a lysosomal marker involved in autophagosome–lysosome fusion, while ferritinophagy (NCOA4) remained unchanged. Early administration of ferrostatin-1 effectively suppressed these pathological changes, preserving both glandular structure and function, as evidenced by the restored AQP5 and AMY2A expression. Collectively, our findings reveal that ferroptosis in estrogen-deficient salivary glands is regulated by mitochondrial instability and aberrant mitophagy, and ferrostatin-1 mitigates this cascade through multi-level mitochondrial protection. These results highlight ferrostatin-1 as a promising preventive agent against menopause-associated salivary gland dysfunction, with broader implications for organ-specific ferroptosis modulation.
Keywords: menopause; ferroptosis; salivary gland dysfunction; mitochondria; mitophagy menopause; ferroptosis; salivary gland dysfunction; mitochondria; mitophagy

Share and Cite

MDPI and ACS Style

Park, G.C.; Bang, S.-Y.; Kim, J.M.; Shin, S.-C.; Cheon, Y.-i.; Park, H.; Suh, S.; Cho, J.H.; Sung, E.-S.; Lee, M.; et al. Ferrostatin-1 Prevents Salivary Gland Dysfunction in an Ovariectomized Rat Model by Suppressing Mitophagy-Driven Ferroptosis. Antioxidants 2025, 14, 1058. https://doi.org/10.3390/antiox14091058

AMA Style

Park GC, Bang S-Y, Kim JM, Shin S-C, Cheon Y-i, Park H, Suh S, Cho JH, Sung E-S, Lee M, et al. Ferrostatin-1 Prevents Salivary Gland Dysfunction in an Ovariectomized Rat Model by Suppressing Mitophagy-Driven Ferroptosis. Antioxidants. 2025; 14(9):1058. https://doi.org/10.3390/antiox14091058

Chicago/Turabian Style

Park, Gi Cheol, Soo-Young Bang, Ji Min Kim, Sung-Chan Shin, Yong-il Cheon, Hanaro Park, Sunghwan Suh, Jung Hwan Cho, Eui-Suk Sung, Minhyung Lee, and et al. 2025. "Ferrostatin-1 Prevents Salivary Gland Dysfunction in an Ovariectomized Rat Model by Suppressing Mitophagy-Driven Ferroptosis" Antioxidants 14, no. 9: 1058. https://doi.org/10.3390/antiox14091058

APA Style

Park, G. C., Bang, S.-Y., Kim, J. M., Shin, S.-C., Cheon, Y.-i., Park, H., Suh, S., Cho, J. H., Sung, E.-S., Lee, M., Lee, J.-C., & Lee, B.-J. (2025). Ferrostatin-1 Prevents Salivary Gland Dysfunction in an Ovariectomized Rat Model by Suppressing Mitophagy-Driven Ferroptosis. Antioxidants, 14(9), 1058. https://doi.org/10.3390/antiox14091058

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