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While corticosteroids use and alcohol consumption are known risk factors, the pathophysiology, especially in idiopathic cases, which account for one-third population, remains unclear. This study aimed to investigate the potential role of human cytomegalovirus (HCMV) reactivation in the pathogenesis of ONFH, focusing on its presence, distribution, and reactivation status. Blood and femoral head samples were obtained from ONFH patients and fracture controls. Human cytomegalovirus exposure was assessed through serology and viral DNA quantification, and reactivation was confirmed by gB immunohistochemistry and IE-1 mRNA RT-qPCR. Tissue samples from different regions of the femoral head (necrotic, transitional, and healthy zones) were analyzed for viral content, reactivation, and localization. Results showed significantly higher HCMV DNA levels in necrotic and transitional zones of ONFH, strongly correlated with lesion volume. Furthermore, gB localization was predominantly found in the microvascular structures, such as small vessels and capillaries, suggesting that HCMV reactivation may contribute to microvascular damage and ischemia. IE-1 transcripts, markers of viral reactivation, further confirmed reactivation. Notably, HCMV reactivation was observed across all ONFH etiologies\u2014corticosteroid-related, alcohol-related, and idiopathic\u2014indicating its broad involvement in ONFH progression. This study provides the first clinical evidence linking HCMV reactivation to ONFH, offering potential therapeutic avenues, including antiviral treatments, to address this condition.<\/jats:p>","DOI":"10.1093\/jbmr\/zjaf205","type":"journal-article","created":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T12:27:37Z","timestamp":1767529657000},"page":"751-761","source":"Crossref","is-referenced-by-count":1,"title":["Osteonecrosis of the femoral head is associated with cytomegalovirus reactivation"],"prefix":"10.1093","volume":"41","author":[{"given":"Rui","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital , Nanjing 210029 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejiao","family":"Tian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University , Nanjing 210023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University , Nanjing 210023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Kong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University , Nanjing 210023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4645-0958","authenticated-orcid":false,"given":"Zhenzhen","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University , Nanjing 210023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University , Nanjing 210023 ,","place":["China"]},{"name":"Chemistry and Biomedicine Innovative Center, Nanjing University , Nanjing 210023 ,","place":["China"]},{"name":"National Resource Center for Mutant Mice (NRCMM), Nanjing University , Nanjing 210023 ,","place":["China"]},{"name":"Department of Project Technology, NJU Xishan Institute of Applied Biotechnology , Wuxi 214101 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"issue":"8","key":"2026081703270351900_ref1","doi-asserted-by":"crossref","first-page":"590","DOI":"10.5312\/wjo.v6.i8.590","article-title":"Current concepts on osteonecrosis of the femoral head","volume":"6","author":"Moya-Angeler","year":"2015","journal-title":"World J Orthop"},{"issue":"10213","key":"2026081703270351900_ref2","doi-asserted-by":"crossref","first-page":"e38","DOI":"10.1016\/S0140-6736(19)32687-X","article-title":"Now you see it: progressive radiographic findings in avascular necrosis of the hip","volume":"394","author":"Stirling","year":"2019","journal-title":"Lancet"},{"issue":"3","key":"2026081703270351900_ref3","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1302\/0301-620X.95B3.30856","article-title":"The effect of alcohol intake and the use of oral corticosteroids on the risk of idiopathic osteonecrosis of the femoral head: a case-control study in Japan","volume":"95-B","author":"Fukushima","year":"2013","journal-title":"Bone Joint J"},{"issue":"3","key":"2026081703270351900_ref4","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s12178-015-9277-8","article-title":"Pathophysiology and risk factors for osteonecrosis","volume":"8","author":"Shah","year":"2015","journal-title":"Curr Rev Musculoskelet Med"},{"issue":"1","key":"2026081703270351900_ref5","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1056\/NEJMcp1012926","article-title":"Clinical practice. 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