한빛사논문
부산대학교 치의학전문대학원
Su-Jeong Oh 1,2,3, Ye Young Shin 1,4, Ji-Su Ahn 1, Hee-Jeong Park 1,2,3, Min-Jung Kang 1, Tae-Hoon Shin 5, Byung-Chul Lee 6,7, Won Kyu Kim 8,9,10, Jung-Min Oh 1, Dongjun Lee 11, Yun Hak Kim 12, Ji Min Kim 13, Eui-Suk Sung 14, Eun-Woo Lee 15,16, Jee-Heon Jeong 17, Byung-Joo Lee 13,* Yoojin Seo 1,* and Hyung-Sik Kim 1,2,3,*
1Department of Oral Biochemistry, Dental and Life Science Institute,School of Dentistry Pusan National University Yangsan 50612, Republic of Korea
2Department of Life Science in Dentistry School of Dentistry Pusan National University Yangsan 50612, Republic of Korea
3Education and Research Team for Life Science on Dentistry Pusan National University Yangsan 50612, Republic of Korea
4Stem Cell and Regenerative Bioengineering Institute Global R&D Center Kangstem Biotech Co. Ltd.Seoul 08590, Republic of Korea
5Department of Laboratory Animal Medicine College of Veterinary Medicine and Veterinary Medical Research Institute Jeju National University Jeju-si 63243, Republic of Korea
6Department of Biological Sciences Sookmyung Women’s University Seoul 04310, Republic of Korea
7Research Institute of Women’s Health Sookmyung Women’s University Seoul 04310, Republic of Korea
8Natural Product Research CenterKorea Institute of Science andTechnology (KIST)Gangneung 25451, Republic of Korea
9Department of Convergence MedicineYonsei University Wonju College of MedicineWonju 26426, Republic of Korea
10Division of Natural Products Applied Science University of Science and Technology (UST)Daejeon 34113, Republic of Korea
11Department of Convergence Medicine Pusan National University School of Medicine Yangsan 50612, Republic of Korea
12Department of Anatomy Pusan National University School of Medicine Yangsan 50612, Republic of Korea
13Department of Otorhinolaryngology-Head and Neck Surgery Pusan National University School of Medicine and Biomedical Research Institute Pusan National University Hospital Busan 49241, Republic of Korea
14Department of Otorhinolaryngology-Head and Neck Surgery Biomedical Research Institute Pusan National University School of Medicine Yangsan Pusan National University Hospital Yangsan 50612, Republic of Korea
15Metabolic Regulation Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon 34141, Republic of Korea
16School of Pharmacy Sungkyunkwan University Suwon 16419, Republic of Korea
17Department of Precision Medicine School of Medicine Sungkyunkwan University Suwon 16419, Republic of Korea
†S.-J.O. and Y.Y.S. contributed equally to this work.
*Corresponding authors: correspondence to Byung-Joo Lee, Yoojin Seo or Hyung-Sik Kim
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.
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