Proteome-Wide Mendelian Randomization Implicates Shared Necroptosis-Ferroptosis Effectors in Causal Pathways of
Wu Yan1, Wang Jianhong1,2, Jiang Wen1
1Department of Neurology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China.
Abstract:
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.
Insights
This study confirms ferroptosis and necroptosis pathways are causal in multiple sclerosis (MS) risk. Key proteins like IFNA4 and TNFAIP3, along with regulators such as APOE, are identified as potential therapeutic targets for MS.
Area of Science:
- Neuroimmunology
- Genetics
- Cellular Biology
Background:
- Multiple sclerosis (MS) is a chronic neurodegenerative disease with suspected links to ferroptosis and necroptosis, but causal evidence is lacking.
- Understanding the genetic and molecular drivers of MS susceptibility is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the causal relationships between ferroptosis/necroptosis pathways, their regulators, immune interactions, and MS risk using a proteome-wide Mendelian randomization approach.
- To validate findings using transcriptomic data and identify potential therapeutic targets.
Main Methods:
- Proteome-wide Mendelian randomization (MR) was employed to assess causal links between protein expression and MS risk.
- Bulk and single-cell RNA sequencing were used for transcriptomic validation.
- Mediation analyses were conducted to elucidate causal pathways.
Main Results:
- IFNA4 and TNFAIP3 were identified as key causal proteins in ferroptosis/necroptosis pathways influencing MS risk.
- Fifteen upstream regulators, including APOE, were significantly associated with MS.
- Ceruloplasmin (CP) was found to be upregulated in MS microglia and lesions.
- Two complete causal pathways were established: one mediated by IFNA4 and another driven by APOE via TNFAIP3.
Conclusions:
- Ferroptosis and necroptosis pathways are causally implicated in MS susceptibility.
- TNFAIP3, IFNA4, CP, and APOE represent promising therapeutic targets for MS intervention.
