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Despite their high prevalence and significant impact on quality of life, the biological mechanisms underlying pain chronification in TMD remain incompletely understood. Growing evidence indicates that persistent TMD-related pain arises from complex interactions among inflammatory signaling, oxidative stress, neuroendocrine dysregulation, and epigenetic modulation of gene expression. This integrative narrative review synthesizes current clinical and preclinical evidence from molecular biology, neuroendocrinology, and epigenetics to elucidate the biomolecular mechanisms involved in chronic TMD pain. Studies consistently report elevated proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor-\u03b1, alongside increased oxidative stress markers, including malondialdehyde and 8-hydroxy-2\u2032-deoxyguanosine, accompanied by reduced antioxidant capacity in saliva and serum. Alterations in neuroendocrine mediators, particularly dysregulation of the hypothalamic\u2013pituitary\u2013adrenal axis and reduced levels of neurotrophic factors such as brain-derived neurotrophic factor and nerve growth factor, appear to contribute to central sensitization and impaired neuroplasticity. In parallel, epigenetic mechanisms\u2014including DNA methylation of pain- and stress-related genes (e.g.,\n                    <jats:italic>COMT<\/jats:italic>\n                    and\n                    <jats:italic>TNF\u03b1<\/jats:italic>\n                    ) and differential expression of microRNAs such as miR-140-5p and miR-21-5p\u2014emerge as key modulators of pain susceptibility, persistence, and sex-related differences in clinical presentation. By integrating biomolecular, neuroendocrine, and epigenetic evidence, this review highlights biological signatures associated with chronic TMD pain and discusses their relevance for mechanistic understanding, biomarker discovery, and the development of biologically informed strategies for individualized pain management.\n                  <\/jats:p>","DOI":"10.1007\/s11033-026-11739-5","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T09:29:00Z","timestamp":1775122140000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Epigenetic and biomolecular mechanisms in chronic temporomandibular disorder\u2013related pain: an integrative review"],"prefix":"10.1007","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8050-4396","authenticated-orcid":false,"given":"La\u00eds Valencise","family":"Magri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4943-1242","authenticated-orcid":false,"given":"Melissa de Oliveira","family":"Melchior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4420-6457","authenticated-orcid":false,"given":"Victor Hugo Alves","family":"Ribeiro-Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9889-1790","authenticated-orcid":false,"given":"Jardel Francisco","family":"Mazzi-Chaves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9497-0005","authenticated-orcid":false,"given":"Kranya Victoria","family":"D\u00edaz-Serrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7475-6650","authenticated-orcid":false,"given":"Edilaine Cristina Silva","family":"Gherardi-Donato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1762-2730","authenticated-orcid":false,"given":"Christie Ramos Andrade","family":"Leite-Panissi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"11739_CR1","doi-asserted-by":"publisher","first-page":"1509845","DOI":"10.3389\/fneur.2024.1509845","volume":"15","author":"J - Ku\u0107","year":"2025","unstructured":"Ku\u0107 J, Szarejko KD, Maciejczyk M, Dymicka-Piekarska V, \u017bendzian-Piotrowska M, Zalewska A (2025) Oxidative imbalance as a co-player in jaw functional limitations and biopsychosocial profile in patients with temporomandibular disorder-myofascial pain with referral. 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