TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions

Despite the high incidence of dry mouth in postmenopausal women, its underlying mechanisms and therapeutic interventions remain underexplored. Using ovariectomized (OVX) mouse models, here this study identifies ferroptosis, an iron-dependent regulated cell death, as a central mechanism driving postmenopausal salivary gland (SG) dysfunction. In the OVX-SGs, TGFβ signaling pathway is enhanced with the aberrant TGFβ2 expression in SG mesenchymal cells. Intriguingly, TGFβ2 treatment reduces iron-storing ferritin levels, leading to lipid peroxidation and ferroptotic death in SG epithelial organoids (SGOs). Mechanistically, TGFβ2 promotes the autophagy-mediated ferritin degradation, so-called ferritinophagy. A notable overexpression of the type III TGFβ receptor (TβRIII) is found in the OVX-SGs and TGFβ2-treated SGOs, while the silencing of TβRIII mitigates the ferroptosis-mediated deleterious effects of TGFβ2 on SGOs. Finally, administration of ferroptosis inhibitor, Liproxstatin-1 (Lip-1), improves saliva secretion in OVX mice. Present findings collectively suggest a link between TGFβ signaling, ferroptosis, and SG injury, offering new therapeutic avenues for postmenopausal xerostomia.

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Publication Details

Journal
Advanced Science
Published
2024-10-31
DOI
https://doi.org/10.1002/advs.202400660
Citations
4
Primary Topic
Cancer-related molecular mechanisms research
Type
article
Field-Weighted Citation Impact
1.14
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article

TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions

Eui‐Suk Sung, Jee‐Heon Jeong, Hyung‐Sik Kim, Taekyun Shin et al.
4 citations
Advanced Science
Cancer-related molecular mechanisms research
1.14
article

TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions

Eui‐Suk Sung, Jee‐Heon Jeong, Hyung‐Sik Kim, Taekyun Shin, H.J. Park, Min‐Jung Kang, Ji‐Su Ahn, Byung‐Chul Lee, Ye Young Shin, Eun‐Woo Lee, Jung‐Min Oh, Yun Hak Kim, Su‐Jeong Oh, Dongjun Lee, Ji Min Kim, Yoojin Seo, Won Kyu Kim
article en
4 citations

Abstract

Despite the high incidence of dry mouth in postmenopausal women, its underlying mechanisms and therapeutic interventions remain underexplored. Using ovariectomized (OVX) mouse models, here this study identifies ferroptosis, an iron-dependent regulated cell death, as a central mechanism driving postmenopausal salivary gland (SG) dysfunction. In the OVX-SGs, TGFβ signaling pathway is enhanced with the aberrant TGFβ2 expression in SG mesenchymal cells. Intriguingly, TGFβ2 treatment reduces iron-storing ferritin levels, leading to lipid peroxidation and ferroptotic death in SG epithelial organoids (SGOs). Mechanistically, TGFβ2 promotes the autophagy-mediated ferritin degradation, so-called ferritinophagy. A notable overexpression of the type III TGFβ receptor (TβRIII) is found in the OVX-SGs and TGFβ2-treated SGOs, while the silencing of TβRIII mitigates the ferroptosis-mediated deleterious effects of TGFβ2 on SGOs. Finally, administration of ferroptosis inhibitor, Liproxstatin-1 (Lip-1), improves saliva secretion in OVX mice. Present findings collectively suggest a link between TGFβ signaling, ferroptosis, and SG injury, offering new therapeutic avenues for postmenopausal xerostomia.

Advanced ScienceVol. 11(47)
Yonsei University (KR), Sookmyung Women's University (KR), Cell Biotech (South Korea) (KR), Pusan National University Hospital (KR), Pusan National University Yangsan Hospital (KR), Pusan National University (KR), Korea Institute of Science and Technology (KR), Korea Research Institute of Bioscience and Biotechnology (KR), Jeju National University (KR), Sungkyunkwan University (KR), Korea University of Science and Technology (KR)
Good health and well-being
Openalex Percentile: Top 21%
Cancer-related molecular mechanisms research
1.14
DOIOpen Access PDFOpenAlex
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