TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions
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 driv...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202400660 |
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| author | Su‐Jeong Oh Ye Young Shin Ji‐Su Ahn Hee‐Jeong Park Min‐Jung Kang Tae‐Hoon Shin Byung‐Chul Lee Won Kyu Kim Jung‐Min Oh Dongjun Lee Yun Hak Kim Ji Min Kim Eui‐Suk Sung Eun‐Woo Lee Jee‐Heon Jeong Byung‐Joo Lee Yoojin Seo Hyung‐Sik Kim |
| author_facet | Su‐Jeong Oh Ye Young Shin Ji‐Su Ahn Hee‐Jeong Park Min‐Jung Kang Tae‐Hoon Shin Byung‐Chul Lee Won Kyu Kim Jung‐Min Oh Dongjun Lee Yun Hak Kim Ji Min Kim Eui‐Suk Sung Eun‐Woo Lee Jee‐Heon Jeong Byung‐Joo Lee Yoojin Seo Hyung‐Sik Kim |
| author_sort | Su‐Jeong Oh |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7ba0b6f787f741d1820472fa17c7037c |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-7ba0b6f787f741d1820472fa17c7037c2025-08-20T01:58:42ZengWileyAdvanced Science2198-38442024-12-011147n/an/a10.1002/advs.202400660TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal ConditionsSu‐Jeong Oh0Ye Young Shin1Ji‐Su Ahn2Hee‐Jeong Park3Min‐Jung Kang4Tae‐Hoon Shin5Byung‐Chul Lee6Won Kyu Kim7Jung‐Min Oh8Dongjun Lee9Yun Hak Kim10Ji Min Kim11Eui‐Suk Sung12Eun‐Woo Lee13Jee‐Heon Jeong14Byung‐Joo Lee15Yoojin Seo16Hyung‐Sik Kim17Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University Yangsan 50612 Republic of KoreaDepartment of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University Yangsan 50612 Republic of KoreaDepartment of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University Yangsan 50612 Republic of KoreaDepartment of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University Yangsan 50612 Republic of KoreaDepartment of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University Yangsan 50612 Republic of KoreaDepartment of Laboratory Animal Medicine College of Veterinary Medicine and Veterinary Medical Research Institute Jeju National University Jeju‐si 63243 Republic of KoreaDepartment of Biological Sciences Sookmyung Women's University Seoul 04310 Republic of KoreaNatural Product Research Center Korea Institute of Science andTechnology (KIST) Gangneung 25451 Republic of KoreaDepartment of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University Yangsan 50612 Republic of KoreaDepartment of Convergence Medicine Pusan National University School of Medicine Yangsan 50612 Republic of KoreaDepartment of Anatomy Pusan National University School of Medicine Yangsan 50612 Republic of KoreaDepartment of Otorhinolaryngology‐Head and Neck Surgery Pusan National University School of Medicine and Biomedical Research Institute Pusan National University Hospital Busan 49241 Republic of KoreaDepartment of Otorhinolaryngology‐Head and Neck Surgery Biomedical Research Institute Pusan National University School of Medicine Yangsan Pusan National University Hospital Yangsan 50612 Republic of KoreaMetabolic Regulation Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon 34141 Republic of KoreaDepartment of Precision Medicine School of Medicine Sungkyunkwan University Suwon 16419 Republic of KoreaDepartment of Otorhinolaryngology‐Head and Neck Surgery Pusan National University School of Medicine and Biomedical Research Institute Pusan National University Hospital Busan 49241 Republic of KoreaDepartment of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University Yangsan 50612 Republic of KoreaDepartment of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University Yangsan 50612 Republic of KoreaAbstract 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.https://doi.org/10.1002/advs.202400660estrogenferroptosisorganoidssalivary glandTGFβ2xerostomia |
| spellingShingle | Su‐Jeong Oh Ye Young Shin Ji‐Su Ahn Hee‐Jeong Park Min‐Jung Kang Tae‐Hoon Shin Byung‐Chul Lee Won Kyu Kim Jung‐Min Oh Dongjun Lee Yun Hak Kim Ji Min Kim Eui‐Suk Sung Eun‐Woo Lee Jee‐Heon Jeong Byung‐Joo Lee Yoojin Seo Hyung‐Sik Kim TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions Advanced Science estrogen ferroptosis organoids salivary gland TGFβ2 xerostomia |
| title | TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions |
| title_full | TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions |
| title_fullStr | TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions |
| title_full_unstemmed | TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions |
| title_short | TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions |
| title_sort | tgfβ2 driven ferritin degradation and subsequent ferroptosis underlie salivary gland dysfunction in postmenopausal conditions |
| topic | estrogen ferroptosis organoids salivary gland TGFβ2 xerostomia |
| url | https://doi.org/10.1002/advs.202400660 |
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