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As chondrocytes reside in an avascular microenvironment inside the cartilage matrix, energy production via glycolysis is crucial for their survival. This study investigated the role of the key glycolytic enzyme Hexokinase 2 (HK2) in TMJOA pathogenesis and the therapeutic potential of dental pulp stem cell-derived extracellular vesicles (DPSC-EVs). In a rat experimental TMJOA model induced by monosodium iodoacetate (MIA) intra-articular injection, we observed a significantly decreased expression of HK2 along with cartilage matrix degradation. In the in vitro study, MIA induced chondrocyte apoptosis with caspase-3 activation, accompanied by impaired glycolytic function. Intervention with DPSC-EVs effectively rescued the expression of HK2 within chondrocytes, leading to a notable restoration of cellular glycolysis. Consequently, DPSC-EV treatment markedly attenuated the progression of TMJOA by reducing chondrocyte apoptosis and improved cartilage integrity. Our findings demonstrated that DPSC-EVs represent a promising cell-free therapeutic strategy for TMJOA, exerting their protective effects by targeting HK2, thereby preserving chondrocyte viability and attenuating osteoarthritis development.<\/jats:p>","DOI":"10.3390\/biom16040490","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T10:07:13Z","timestamp":1774433233000},"page":"490","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dental Pulp Stem Cell-Derived Extracellular Vesicles Attenuated Chondrocyte Apoptosis in Early Temporomandibular Joint Osteoarthritis via Regulating Hexokinase 2"],"prefix":"10.3390","volume":"16","author":[{"given":"Shengjie","family":"Cui","sequence":"first","affiliation":[{"name":"Department of General Dentistry, 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, Beijing 100081, China"},{"name":"Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9792-4749","authenticated-orcid":false,"given":"Yu","family":"Fu","sequence":"additional","affiliation":[{"name":"Fourth Clinical Department, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8211-1887","authenticated-orcid":false,"given":"Yanning","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieni","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuedong","family":"Wang","sequence":"additional","affiliation":[{"name":"Center of Stomatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing 102218, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13075-025-03506-x","article-title":"Akt2 inhibition alleviates temporomandibular joint osteoarthritis by preventing subchondral bone loss","volume":"27","author":"Feng","year":"2025","journal-title":"Arthritis Res. 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