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Using ovariectomized (OVX) mouse models, here this study identifies ferroptosis, an iron\u2010dependent regulated cell death, as a central mechanism driving postmenopausal salivary gland (SG) dysfunction. In the OVX\u2010SGs, TGF\u03b2 signaling pathway is enhanced with the aberrant TGF\u03b22 expression in SG mesenchymal cells. Intriguingly, TGF\u03b22 treatment reduces iron\u2010storing ferritin levels, leading to lipid peroxidation and ferroptotic death in SG epithelial organoids (SGOs). Mechanistically, TGF\u03b22 promotes the autophagy\u2010mediated ferritin degradation, so\u2010called ferritinophagy. A notable overexpression of the type III TGF\u03b2 receptor (T\u03b2RIII) is found in the OVX\u2010SGs and TGF\u03b22\u2010treated SGOs, while the silencing of T\u03b2RIII mitigates the ferroptosis\u2010mediated deleterious effects of TGF\u03b22 on SGOs. Finally, administration of ferroptosis inhibitor, Liproxstatin\u20101 (Lip\u20101), improves saliva secretion in OVX mice. Present findings collectively suggest a link between TGF\u03b2 signaling, ferroptosis, and SG injury, offering new therapeutic avenues for postmenopausal xerostomia.<\/jats:p>","DOI":"10.1002\/advs.202400660","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T19:55:28Z","timestamp":1730404528000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["TGF\u03b22\u2010Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions"],"prefix":"10.1002","volume":"11","author":[{"given":"Su\u2010Jeong","family":"Oh","sequence":"first","affiliation":[{"name":"Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University  Yangsan 50612 Republic of Korea"},{"name":"Department of Life Science in Dentistry School of Dentistry Pusan National University  Yangsan 50612 Republic of Korea"},{"name":"Education and Research Team for Life Science on Dentistry Pusan National University  Yangsan 50612 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye Young","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University  Yangsan 50612 Republic of Korea"},{"name":"Stem Cell and Regenerative Bioengineering Institute Global R&amp;D Center Kangstem Biotech Co. 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Seoul 08590 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji\u2010Su","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University  Yangsan 50612 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee\u2010Jeong","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry Pusan National University  Yangsan 50612 Republic of Korea"},{"name":"Department of Life Science in Dentistry School of Dentistry Pusan National University  Yangsan 50612 Republic of Korea"},{"name":"Education and Research Team for Life Science on Dentistry Pusan National University  Yangsan 50612 Republic of 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