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Though current research has indicated that transferrin receptor (TFRC) regulating ferroptosis affects the progression of TMJOA, its role in cartilage homeostasis remains unclear. Therefore, we constructed unilateral anterior crossbite (UAC) and cartilage-specific Tfrc conditional knockout (Tfrc-cKO) mice. The expressions of iron transportation-associated genes including TFRC and SLC39A14, and ferroptosis-related markers were detected in TMJ cartilage through immunofluorescence, immunohistochemical staining, western blot, and quantitative real-time PCR (qPCR) assays. Knockdown of Tfrc and knockdown of Drp1 by small interfering RNA in ATDC5 cell line under mechanical overloading were used to investigate the mechanism in vitro through western blot, qPCR, and flow cytometry assays. Deferiprone was utilized to verify the pathway in vitro and in vivo. Both the control and Tfrc-cKO mice with UAC developed cartilage degradation and subchondral bone resorption. While the former showed upregulated TFRC and SLC39A14 expression in condylar chondrocytes, the latter exhibited increased SLC39A14 expression alone with elevated ferroptosis markers. Under normal circumstances, cytoplasmic p53 induced ubiquitinated degradation of SLC39A14 mediated by SIAH1. However, under Tfrc knockdown and mechanical overloading, increased DRP1 expression and its Ser616 phosphorylation promoted mitochondrial p53 translocation and reduced SLC39A14 ubiquitination degradation. Both siDrp1-mediated knockdown and deferiprone treatment modulated DRP1 expression to attenuate mitochondrial p53 translocation and alleviate TMJOA progression by suppressing ferroptosis. Our findings demonstrate the role of TFRC and SLC39A14 in maintenance of cartilage homeostasis with DRP1-mediated mitochondrial p53 translocation, offering insights into potential treatment strategies for TMJOA.<\/jats:p>","DOI":"10.1042\/cs20260714","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T12:46:02Z","timestamp":1780922762000},"page":"1429-1454","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DRP1\/p53 interaction-mediated mitochondrial regulation of TFRC-SLC39A14 drives mechanical overload-induced temporomandibular joint osteoarthritis via ferroptosis"],"prefix":"10.1042","volume":"140","author":[{"given":"Yidi","family":"Wang","sequence":"first","affiliation":[{"name":"1Department of Orthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Guo","sequence":"additional","affiliation":[{"name":"1Department of Orthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Yu","sequence":"additional","affiliation":[{"name":"1Department of Orthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjie","family":"Cui","sequence":"additional","affiliation":[{"name":"2Department of General Dentistry, Peking University School and Hospital of Stomatology, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2000-1198","authenticated-orcid":false,"given":"Xi","family":"Wen","sequence":"additional","affiliation":[{"name":"1Department of Orthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, No.22, Zhongguancun Avenue South, Haidian District, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"2026062407170512000_B1","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"2026062407170512000_B2","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1038\/s41467-019-09491-5","article-title":"Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-\u03baB pathway","volume":"10","author":"Chang","year":"2019","journal-title":"Nat. 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