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Epidemiological data show a 2\u20103\u2010fold increase in neuropsychiatric co\u2010morbidities among individuals with chronic pain, where epigenetic dysregulation serves as a key mechanism linking ongoing pain to emotional disorders. This review systematically explores epigenetic signatures in supraspinal integration hubs, notably the limbic\u2010paralimbic networks and prefrontal regulatory circuits. The identified epigenetic signatures encompass dysregulation of DNA methyltransferases (DNMTs), RNA modifications, histone post\u2010translational modifications and locus\u2010specific alterations, including aberrant methylation at the brain\u2010derived neurotrophic factor (BDNF), opioid \u03bc receptor and transient receptor potential ankyrin 1 (TRPA1) gene loci. Additionally, they involve dysfunction of the glucocorticoid receptor (GR)\/corticotropin\u2010releasing factor (CRF) axis via epigenetic modulation. Building on these findings, we evaluate therapeutic strategies addressing epigenetic dysregulation. While preclinical data demonstrate the efficacy of histone deacetylase (HDAC) and DNMT inhibitors, clinical translation faces significant barriers, including limited blood\u2013brain barrier permeability. Notably, our analysis highlights the benefits of combining pharmacological interventions with non\u2010invasive neuromodulation for enhanced co\u2010morbidity management. Looking forward, this review proposes innovative approaches that leverage CRISPR\u2010based chromatin editing platforms, biomimetic nanocarriers for neuron\u2010specific delivery and closed\u2010loop neuromodulation integrating real\u2010time biomarker feedback, collectively establishing a precision medicine framework for pain or neuropsychiatric co\u2010morbidities.<\/jats:p>","DOI":"10.1111\/bph.70302","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T02:30:51Z","timestamp":1768876251000},"page":"1313-1340","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Epigenetic mechanisms and therapeutic innovations in chronic pain\u2010associated neuropsychiatric co\u2010morbidities"],"prefix":"10.1111","volume":"183","author":[{"given":"Kai","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijia","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Pain and Perioperative Medicine The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, School of Basic Medical Sciences Zhengzhou University  Zhengzhou 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