Proteome‐Wide Mendelian Randomization Implicates Shared Necroptosis–Ferroptosis Effectors in Causal Pathways of Multiple Sclerosis Susceptibility

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-wide Mendelian randomization (MR) to investigate causal links between ferroptosis/necroptosis pathways, their upstream regulators, immune interactions, and MS risk. Transcriptomic validation utilized bulk RNA-seq and single-cell RNA-seq data. MR identified IFNA4 (OR = 0.24) and TNFAIP3 (OR = 2.0) as key causal ferroptosis/necroptosis-related proteins for MS risk. Analysis revealed 15 upstream regulators significantly associated with MS (FDR < 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-mediated 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-driven pathway operating via TNFAIP3, demonstrating significant total effects and near-significant mediator-outcome effects on MS risk. While 59 immune traits were MS-associated, only TNFAIP3 showed a suggestive association with CD27⁺ 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.