{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:37:56Z","timestamp":1789465076491,"version":"build-2803163510"},"reference-count":126,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Theme-based Research Scheme","award":["T12-70323-N"],"award-info":[{"award-number":["T12-70323-N"]}]},{"name":"Health and Medical Research Grant","award":["11222136"],"award-info":[{"award-number":["11222136"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Nasopharyngeal carcinoma (NPC) is a geographically distinct malignancy closely associated with Epstein\u2013Barr virus (EBV) infection and characterized by extensive epigenetic reprogramming within a highly immunosuppressive tumor microenvironment (TME). High-mobility group box 1 (HMGB1), a multifunctional chromatin-binding protein that can also act as an extracellular damage-associated molecular pattern (DAMP), has emerged as an important regulator of genome organization, transcriptional control, cellular stress responses, and immune signaling. Increased HMGB1 expression has been reported in NPC and is associated with adverse clinicopathological features and poor patient outcomes. Emerging evidence suggests that the diverse biological functions of HMGB1 are influenced by post-translational modifications (PTMs), which affect its subcellular localization, molecular interactions, and extracellular signaling functions. Through these regulatory mechanisms, HMGB1 may transition from a nuclear chromatin-associated protein to an extracellular mediator of immune and inflammatory responses. PTMs including acetylation, phosphorylation, glycosylation, oxidation, methylation, and lactylation have been implicated in regulating HMGB1 trafficking and function, although the specific roles of many of these modifications in NPC remain incompletely characterized. In this review, we summarize current evidence regarding HMGB1 PTMs and discuss their potential implications for EBV-associated NPC, with emphasis on nuclear regulation, immune crosstalk, and therapeutic response. We explicitly distinguish findings directly demonstrated in NPC from mechanistic insights derived from other malignancies and related disease models, and identify areas where proposed mechanisms remain hypothesis-generating rather than experimentally validated in NPC. By integrating current evidence with emerging mechanistic concepts, we highlight key knowledge gaps, unresolved questions, and priorities for future research. A better understanding of PTM-dependent HMGB1 regulation may facilitate the development of novel biomarker and therapeutic strategies for EBV-associated NPC.<\/jats:p>","DOI":"10.3390\/ijms27188196","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T08:16:48Z","timestamp":1789460208000},"page":"8196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HMGB1 Post-Translational Modifications in Epstein\u2013Barr Virus-Associated Nasopharyngeal Carcinoma: Current Evidence, Emerging Mechanistic Concepts, and Unresolved Questions"],"prefix":"10.3390","volume":"27","author":[{"given":"Cho Yiu","family":"Lau","sequence":"first","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadija Shahed","family":"Khan","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1304-2854","authenticated-orcid":false,"given":"Dora Lai-Wan","family":"Kwong","sequence":"additional","affiliation":[{"name":"Centre of Cancer Medicine, Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5558-0685","authenticated-orcid":false,"given":"Wei","family":"Dai","sequence":"additional","affiliation":[{"name":"Centre of Cancer Medicine, Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4053-6040","authenticated-orcid":false,"given":"Ngar Woon","family":"Kam","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, China"},{"name":"Centre of Cancer Medicine, Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00432-023-05547-8","article-title":"Nasopharyngeal carcinoma: Nationwide trends in subtype-specific incidence and survival over 3 decades in a non-endemic area","volume":"150","author":"Plaat","year":"2024","journal-title":"J. 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