{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:30:31Z","timestamp":1790814631263,"version":"4.1.0"},"reference-count":97,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cVictor Babe\u015f\u201d University of Medicine and Pharmacy, Timisoara, Romania"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Progressive multiple sclerosis (PMS) represents a distinct clinical and biological entity characterized by compartmentalized neuroinflammation, chronic glial activation, and resistance to conventional immunotherapies. Unlike relapsing MS, PMS is sustained by resident CNS immune networks, where activated microglia and astrocytes orchestrate persistent cytokine signaling\u2014particularly involving TNF-\u03b1, IL-1\u03b2, and IL-6\u2014through self-amplifying feedback loops. In this narrative review, we explore how these cytokines interact with oxidative stress, iron accumulation, mitochondrial dysfunction, and impaired autophagy to drive neurodegeneration. Human-based evidence is integrated with insights from experimental models to clarify translational mechanisms. We also highlight fluid biomarkers (e.g., GFAP, NfL) and imaging modalities (e.g., TSPO-PET, QSM) that reflect glial activity and disease progression in vivo. Age, sex hormones, and immunosenescence are discussed as modulators of cytokine expression. Finally, we review emerging therapeutic strategies that target glial metabolism and cytokine networks rather than peripheral immune cells, offering a systems-based framework for future PMS interventions and personalized disease monitoring.<\/jats:p>","DOI":"10.3390\/ijms26188817","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T14:14:55Z","timestamp":1757513695000},"page":"8817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Glial Cytokine and Metabolic Networks in Progressive Multiple Sclerosis: From Pathophysiology to Biomarkers and Therapeutic Strategies"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3614-9147","authenticated-orcid":false,"given":"Henry Leonard","family":"Hohm","sequence":"first","affiliation":[{"name":"Faculty of Medicine, \u201cVictor Babes\u201d University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasmus","family":"Schuster","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, \u201cVictor Babes\u201d University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor Bogdan","family":"Buciu","sequence":"additional","affiliation":[{"name":"Doctoral School, \u201cVictor Babes\u201d University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis-Mihai","family":"Serban","sequence":"additional","affiliation":[{"name":"Department of Obstetrics-Gynaecology, Discipline of Obstetrics-Gynecology, \u201cVictor Babes\u201d University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8178-0449","authenticated-orcid":false,"given":"Sebastian","family":"Ciurescu","sequence":"additional","affiliation":[{"name":"Doctoral School, \u201cVictor Babes\u201d University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7293-3414","authenticated-orcid":false,"given":"Amalia","family":"Cornea","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Neurology II Division, Victor Babe\u0219 University of Medicine and Pharmacy, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0865-0054","authenticated-orcid":false,"given":"Abhinav","family":"Sharma","sequence":"additional","affiliation":[{"name":"Doctoral School, \u201cVictor Babes\u201d University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania"},{"name":"University Clinic of Internal Medicine and Ambulatory Care, Prevention and Cardiovascular Recovery, Department VI-Cardiology, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 3000041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0489-246X","authenticated-orcid":false,"given":"Daciana","family":"Nistor","sequence":"additional","affiliation":[{"name":"Department of Functional Sciences, Physiology, Center of Immuno-Physiology and Biotechnologies (CIFBIOTEH), \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Centre for Gene and Cellular Therapies in Cancer, 300723 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2824-7182","authenticated-orcid":false,"given":"Nilima Rajpal","family":"Kundnani","sequence":"additional","affiliation":[{"name":"University Clinic of Internal Medicine and Ambulatory Care, Prevention and Cardiovascular Recovery, Department VI-Cardiology, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 3000041 Timisoara, Romania"},{"name":"Research Centre of Timisoara, Institute of Cardiovascular Diseases, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 3000041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Haki, M., Al-Biati, H.A., Al-Tameemi, Z.S., Ali, I.S., and Al-Hussaniy, H.A. 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