{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:30:38Z","timestamp":1790814638007,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["nyaspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann NY Acad Sci"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Multiple sclerosis (MS) is a chronic neurodegenerative disorder for which dysregulated ferroptosis and necroptosis have demonstrated pathological associations but these lack causal validation in disease susceptibility. This study employed proteome\u2010wide Mendelian randomization (MR) to investigate causal links between ferroptosis\/necroptosis pathways, their upstream regulators, immune interactions, and MS risk. Transcriptomic validation utilized bulk RNA\u2010seq and single\u2010cell RNA\u2010seq data. MR identified IFNA4 (OR = 0.24) and TNFAIP3 (OR = 2.0) as key causal ferroptosis\/necroptosis\u2010related proteins for MS risk. Analysis revealed 15 upstream regulators significantly associated with MS (FDR &lt; 0.05; e.g., GZMA, CXCL3, APOE, CFB, CA6, KIR2DL2\/3). Transcriptomic validation consistently identified ceruloplasmin (CP) as upregulated in MS microglia and lesions. Mediation analyses established two complete causal pathways: an IFNA4\u2010mediated pathway wherein five upstream immune regulators (KIR2DL2, KIR2DL3, CFB, GZMA, and CA6) influence MS susceptibility through IFNA4 regulation, with all component effects statistically significant; and an APOE\u2010driven pathway operating via TNFAIP3, demonstrating significant total effects and near\u2010significant mediator\u2010outcome effects on MS risk. While 59 immune traits were MS\u2010associated, only TNFAIP3 showed a suggestive association with CD27\u207a memory B cells. This study establishes ferroptosis\/necroptosis pathways as causal drivers of MS susceptibility, highlighting TNFAIP3, IFNA4, CP, and APOE as therapeutically actionable targets.<\/jats:p>","DOI":"10.1111\/nyas.70162","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T02:26:42Z","timestamp":1765592802000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Proteome\u2010Wide Mendelian Randomization Implicates Shared Necroptosis\u2013Ferroptosis Effectors in Causal Pathways of Multiple Sclerosis Susceptibility"],"prefix":"10.1111","volume":"1556","author":[{"given":"Wu","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Kunming Medical University  Kunming Yunnan People's Republic of 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