{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T15:59:16Z","timestamp":1792684756480,"version":"4.5.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Multiple sclerosis (MS) extends beyond focal autoimmune demyelination, with progressive neurodegeneration and cognitive impairment arising from mechanisms not fully explained by inflammatory lesions alone. We propose the kynurenine pathway (KP) as a unifying immunometabolic interface that translates peripheral inflammation into central neuroaxonal vulnerability. Cytokine-driven induction of indoleamine 2,3-dioxygenase accelerates systemic tryptophan catabolism, increasing circulating kynurenine that crosses the blood\u2013brain barrier via L-type amino acid transporter 1 (LAT1). Within the CNS, microglial kynurenine 3-monooxygenase generates the excitotoxic and pro-oxidant metabolites quinolinic acid and 3-hydroxykynurenine, while astrocytic kynurenine aminotransferases produce the neuroprotective antagonist kynurenic acid. This enzymatic dichotomy creates a dynamic amplification loop that intensifies excitotoxicity, oxidative stress, oligodendrocyte injury, and axonal loss. Clinical evidence shows that kynurenine metabolite ratios correlate with plasma neurofilament light chain, cognitive deficits, obesity-related inflammation, and phenotype-specific exercise responsiveness, underscoring KP plasticity as a potential determinant of disease trajectory. By reframing MS through this immunometabolic lens, the KP emerges as both a mechanistic bridge between inflammation and neurodegeneration and a tractable biomarker system with therapeutic potential.<\/jats:p>","DOI":"10.3389\/fncel.2026.1831349","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T04:35:58Z","timestamp":1779683758000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The kynurenine pathway: an immunometabolic bridge linking systemic inflammation to neuroaxonal vulnerability in multiple sclerosis"],"prefix":"10.3389","volume":"20","author":[{"given":"Jos\u00e9 Luis","family":"Maldonado-Garc\u00eda","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico","place":["Coyoac\u00e1n, Ciudad de M\u00e9xico, Mexico"]},{"name":"Coordinaci\u00f3n Acad\u00e9mica, Licenciatura en Medicina, Escuela de Ciencias de la Salud, Universidad del Valle de M\u00e9xico Campus Coyoac\u00e1n","place":["Coyoac\u00e1n, Ciudad de M\u00e9xico, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lissette Haydee","family":"Garc\u00eda-Mena","sequence":"additional","affiliation":[{"name":"Departamento de Salud Digital, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico","place":["Coyoac\u00e1n, Ciudad de M\u00e9xico, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo Alberto","family":"Ferat-Pel\u00e1ez","sequence":"additional","affiliation":[{"name":"Facultad Mexicana de Medicina, Universidad La Salle","place":["Tlalpan, Ciudad de M\u00e9xico, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilberto","family":"P\u00e9rez-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Laboratorio de Psicoinmunolog\u00eda, Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Becerril-Villanueva","sequence":"additional","affiliation":[{"name":"Laboratorio de Psicoinmunolog\u00eda, Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Argelia Esperanza","family":"Rojas-Mayorqu\u00edn","sequence":"additional","affiliation":[{"name":"Departamento Materno Infantil, Centro Universitario de Tlajomulco, Universidad de Guadalajara","place":["Tlajomulco, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel Iv\u00e1n","family":"Gir\u00f3n-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Laboratorio Nacional LANIIA-NAYARIT, Universidad Aut\u00f3noma de Nayarit","place":["Tepic, Nayarit, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Ortu\u00f1o-Sahag\u00fan","sequence":"additional","affiliation":[{"name":"Laboratorio de Neuroinmunobiolog\u00eda Molecular, Instituto de Neurociencias Traslacionales, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenin","family":"Pav\u00f3n","sequence":"additional","affiliation":[{"name":"Laboratorio de Psicoinmunolog\u00eda, Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1007\/s10072-010-0376-4","article-title":"Cognitive impairment in early stages of multiple sclerosis","volume":"31","author":"Amato","year":"2010","journal-title":"Neurol. 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