{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T16:15:35Z","timestamp":1783354535384,"version":"3.54.6"},"reference-count":43,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006545","name":"NIH","doi-asserted-by":"publisher","award":["5P20MD006988"],"award-info":[{"award-number":["5P20MD006988"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006545","name":"NIH","doi-asserted-by":"publisher","award":["5R25GM060507"],"award-info":[{"award-number":["5R25GM060507"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Neuropathic pain (NP) arises from diverse conditions, including peripheral nerve injury, spinal cord injury (SCI), and painful diabetic neuropathy, yet these disorders share oxidative stress, mitochondrial dysfunction, lipid dysregulation, and altered neuronal excitability. We investigated whether dietary omega-3 polyunsaturated fatty acids modulate ferroptotic stress-associated pathways, defined as lipid peroxidation susceptibility and impaired antioxidant defense rather than overt ferroptotic cell death. Female Sprague\u2013Dawley rats received either a soy oil control diet (SOD) or fish oil omega-3-enriched diet (FOD) before chronic constriction injury (CCI). Behavioral outcomes were assessed using Hargreaves and CatWalk testing, followed by dorsal root ganglion (DRG) RNA sequencing, RT-PCR, and GPX4 ELISA. Previously generated SCI metabolomics and human diabetic serum metabolomic\/lipidomic datasets were re-analyzed for shared pathways. FOD attenuated CCI-induced thermal hypersensitivity and improved gait parameters. DRG transcriptomics showed reduced injury-associated transcriptional disruption, enrichment of selenoamino acid metabolism, nonsense-mediated decay, and ribosomal quality-control pathways, and reduced mitochondrial dysfunction pathway activity. Omega-3 increased Gpx1\/Gpx4 expression and GPX4 protein, reduced pain-associated genes including Scn10a, Piezo2, Trpa1, and Oprm1, and aligned with selenoamino acid enrichment in SCI and human datasets. Human lipidomics showed MG\/DG\/PC\/PE pathway remodeling. These findings support ferroptotic stress as a plausible shared downstream mechanism modulated by omega-3 supplementation across NP models.<\/jats:p>","DOI":"10.3390\/antiox15070852","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:56:42Z","timestamp":1783349802000},"page":"852","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Omega-3 Fatty Acids Attenuate Neuropathic Pain by Modulating Ferroptotic Stress, Selenoamino Acid Metabolism, and Lipid Remodeling"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7844-3192","authenticated-orcid":false,"given":"Viet H.","family":"Dinh","sequence":"first","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magda","family":"Descorbeth","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Zamora","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo-Wen","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cono","family":"Badalamenti","sequence":"additional","affiliation":[{"name":"Blue Zones<sup>\u2122<\/sup> Health, Riverside, CA 92506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6369-4586","authenticated-orcid":false,"given":"Salvador","family":"Soriano","sequence":"additional","affiliation":[{"name":"Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4769-8736","authenticated-orcid":false,"given":"Johnny D.","family":"Figueroa","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6576-785X","authenticated-orcid":false,"given":"Marino De","family":"Le\u00f3n","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8614-8477","authenticated-orcid":false,"given":"Alfonso M.","family":"Dur\u00e1n","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"},{"name":"Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2058738419838383","DOI":"10.1177\/2058738419838383","article-title":"The neuropathic pain: An overview of the current treatment and future therapeutic approaches","volume":"33","author":"Cavalli","year":"2019","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.neuro.051508.135531","article-title":"Neuropathic pain: A maladaptive response of the nervous system to damage","volume":"32","author":"Costigan","year":"2009","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1066","DOI":"10.1097\/PR9.0000000000001066","article-title":"Epidemiology of neuropathic pain: An analysis of prevalence and associated factors in UK Biobank","volume":"8","author":"Baskozos","year":"2023","journal-title":"Pain Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.pain.2007.08.013","article-title":"Prevalence of chronic pain with neuropathic characteristics in the general population","volume":"136","author":"Bouhassira","year":"2008","journal-title":"Pain"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"112099","DOI":"10.1016\/j.diabres.2025.112099","article-title":"Prevalence and risk factors of painful diabetic neuropathy: A systematic review and meta-analysis","volume":"222","author":"Tao","year":"2025","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Zhou, P., Zhou, J.S., Li, J.J., Qin, L., Hu, W.F., Zhang, X.Y., Wang, J.X., and Shi, Z. (2025). Prevalence and risk factors for painful diabetic peripheral neuropathy: A systematic review and meta-analysis. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1564867"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/s41392-025-02175-1","article-title":"Diabetic neuropathy: Cutting-edge research and future directions","volume":"10","author":"Yang","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Davidson, E., Obrosov, O., Coppey, L., and Yorek, M. (2025). Omega-3 Polyunsaturated Fatty Acids (PUFAs) and Diabetic Peripheral Neuropathy: A Pre-Clinical Study Examining the Effect of Omega-3 PUFAs from Fish Oil, Krill Oil, Algae or Pharmaceutical-Derived Ethyl Esters Using Type 2 Diabetic Rats. Biomedicines, 13.","DOI":"10.3390\/biomedicines13071607"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e18240","DOI":"10.1111\/jcmm.18240","article-title":"Electroacupuncture suppresses neuronal ferroptosis to relieve chronic neuropathic pain","volume":"28","author":"Xue","year":"2024","journal-title":"J. Cell. Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Li, L., Guo, L., Gao, R., Yao, M., Qu, X., Sun, G., Fu, Q., Hu, C., and Han, G. (2023). Ferroptosis: A new regulatory mechanism in neuropathic pain. Front. Aging Neurosci., 15.","DOI":"10.3389\/fnagi.2023.1206851"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2013.09.012","article-title":"Metabolomics uncovers dietary omega-3 fatty acid-derived metabolites implicated in anti-nociceptive responses after experimental spinal cord injury","volume":"255","author":"Figueroa","year":"2013","journal-title":"Neuroscience"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1016\/j.chembiol.2020.10.010","article-title":"Using the Oxytosis\/Ferroptosis Pathway to Understand and Treat Age-Associated Neurodegenerative Diseases","volume":"27","author":"Maher","year":"2020","journal-title":"Cell Chem. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1083\/jcb.141.6.1423","article-title":"The regulation of reactive oxygen species production during programmed cell death","volume":"141","author":"Tan","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Dar, N.J., Soriano Castell, D., Bhat, S.A., and Maher, P. (2024). Editorial: Oxytosis\/ferroptosis: Unraveling the mechanisms and its multifaceted role in neurodegenerative diseases. Front. Mol. Neurosci., 17.","DOI":"10.3389\/fnmol.2024.1547301"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"109","DOI":"10.2147\/DMSO.S187268","article-title":"Effects of omega-3 polyunsaturated fatty-acid supplementation on neuropathic pain symptoms and sphingosine levels in Mexican-Americans with type 2 diabetes","volume":"12","author":"Salto","year":"2019","journal-title":"Diabetes Metab. Syndr. Obes. Targets Ther."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Dur\u00e1n, A.M., Beeson, W.L., Firek, A., Cordero-MacIntyre, Z., and De Le\u00f3n, M. (2022). Dietary Omega-3 Polyunsaturated Fatty-Acid Supplementation Upregulates Protective Cellular Pathways in Patients with Type 2 Diabetes Exhibiting Improvement in Painful Diabetic Neuropathy. Nutrients, 14.","DOI":"10.3390\/nu14040761"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"104462","DOI":"10.1016\/j.phrs.2019.104462","article-title":"Omega-3 fatty acids supplementation and oxidative stress parameters: A systematic review and meta-analysis of clinical trials","volume":"149","author":"Heshmati","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dur\u00e1n, A.M., Zamora, F., and De Le\u00f3n, M. (2024). Dietary Docosahexaenoic Acid-Rich Supplementation Decreases Neurotoxic Lipid Mediators in Participants with Type 2 Diabetes and Neuropathic Pain. Nutrients, 16.","DOI":"10.3390\/nu16234025"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1089\/neu.2012.2718","article-title":"Dietary omega-3 polyunsaturated fatty acids improve the neurolipidome and restore the DHA status while promoting functional recovery after experimental spinal cord injury","volume":"30","author":"Figueroa","year":"2013","journal-title":"J. Neurotrauma"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Austin, P.J., Wu, A., and Moalem-Taylor, G. (2012). Chronic constriction of the sciatic nerve and pain hypersensitivity testing in rats. J. Vis. Exp., 3393.","DOI":"10.3791\/3393-v"},{"key":"ref_22","first-page":"e2506","article-title":"Assessment of Thermal Pain Sensation in Rats and Mice Using the Hargreaves Test","volume":"7","author":"Cheah","year":"2017","journal-title":"Bio Protoc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1758-2946-2-9","article-title":"Organization of GC\/MS and LC\/MS metabolomics data into chemical libraries","volume":"2","author":"Dehaven","year":"2010","journal-title":"J. Cheminform."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1089\/neu.2015.4186","article-title":"Fatty Acid Binding Protein 5 Modulates Docosahexaenoic Acid-Induced Recovery in Rats Undergoing Spinal Cord Injury","volume":"33","author":"Figueroa","year":"2016","journal-title":"J. Neurotrauma"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1194\/jlr.D023036","article-title":"The BUME method: A novel automated chloroform-free 96-well total lipid extraction method for blood plasma","volume":"53","author":"Forsberg","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_26","unstructured":"Little, R.J.A., and Rubin, D.B. (2019). Statistical Analysis with Missing Data, Wiley Blackwell. [3rd ed.]."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1016\/j.cell.2022.06.003","article-title":"Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications","volume":"185","author":"Stockwell","year":"2022","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s40122-024-00673-8","article-title":"Mechanisms and Therapeutic Potential of GPX4 in Pain Modulation","volume":"14","author":"Fan","year":"2025","journal-title":"Pain Ther."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Sun, D., Wang, L., Wu, Y., Yu, Y., Yao, Y., Yang, H., and Hao, C. (2025). Lipid metabolism in ferroptosis: Mechanistic insights and therapeutic potential. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1545339"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/s42255-020-0224-7","article-title":"Selenium detoxification is required for cancer-cell survival","volume":"2","author":"Carlisle","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1038\/s41594-024-01329-z","article-title":"PRDX6 augments selenium utilization to limit iron toxicity and ferroptosis","volume":"31","author":"Fujita","year":"2024","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Sanchez, K.L., Kim, J., White, J.B., Tolan, A., Rajagopal, N.P., Anderson, D.W., Shin, A.N., Shin, S.D., Currais, A., and Soriano-Castell, D. (2025). Evidence of Oxytosis\/Ferroptosis in Niemann-Pick Disease Type C. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26072915"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"White, J.B., Sanchez, K.L., Currais, A., Soriano-Castell, D., Maher, P., and Soriano, S. (2025). Ferroptosis and Charcot-Marie-Tooth Disease 1A: Emerging Evidence for a Pathogenic Association. Antioxidants, 14.","DOI":"10.3390\/antiox14030331"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Maher, P., Soriano-Castell, D., Dar, N.J., Soriano, S., and Currais, A. (2025). Ferroptosis-related stress during aging and its relevance to disease. GeroScience, Online ahead of print.","DOI":"10.1007\/s11357-025-01929-7"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.15252\/embr.201642195","article-title":"The integrated stress response","volume":"17","author":"Koryga","year":"2016","journal-title":"EMBO Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","article-title":"The integrated stress response: From mechanism to disease","volume":"368","author":"Walter","year":"2020","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Xie, Y.F. (2025). Nav1.8 and Chronic Pain: From Laboratory Animals to Clinical Patients. Biomolecules, 15.","DOI":"10.3390\/biom15050694"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1016\/j.neuron.2025.03.006","article-title":"Vascular motion in the dorsal root ganglion sensed by Piezo2 in sensory neurons triggers episodic pain","volume":"113","author":"Xie","year":"2025","journal-title":"Neuron"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3175","DOI":"10.1007\/s12035-023-03270-6","article-title":"Methyl Ferulic Acid Alleviates Neuropathic Pain by Inhibiting Nox4-induced Ferroptosis in Dorsal Root Ganglia Neurons in Rats","volume":"60","author":"Liu","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"103930","DOI":"10.1016\/j.redox.2025.103930","article-title":"Ferredoxins: Master regulators in mitochondrial redox homeostasis and programmed cell death","volume":"88","author":"Lu","year":"2025","journal-title":"Redox Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1007\/s12011-025-04798-5","article-title":"Integrated Multi-omics and Experimental Validation Reveal FDX1\/LIAS-Mediated Cuproptosis as a Potential Driver of Diabetic Kidney Disease","volume":"204","author":"Liu","year":"2026","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nchembio.2238","article-title":"Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis","volume":"13","author":"Kagan","year":"2017","journal-title":"Nat. Chem. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.tcb.2023.05.003","article-title":"Regulation of ferroptosis by lipid metabolism","volume":"33","author":"Pope","year":"2023","journal-title":"Trends Cell Biol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/7\/852\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T15:27:18Z","timestamp":1783351638000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/7\/852"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,6]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["antiox15070852"],"URL":"https:\/\/doi.org\/10.3390\/antiox15070852","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,6]]}}}