Mendelian Randomization Reveals Potential Drug Targets for Multiple Sclerosis Targeting Ferroptosis

INTRODUCTION: Multiple sclerosis (MS) is a multifactorial autoimmune condition, and existing medications offer limited efficacy, especially regarding the control of disease progression. Our previous research has suggested a significant role for ferroptosis in the mechanism of MS, making it a promising therapeutic target. METHODS: To identify potential treatment targets related to ferroptosis, we conducted Mendelian randomization analysis. We used transcription and proteomic data for 511 ferroptosis-related proteins extracted from 49 tissues in GTEx v8 and deCODE data to derive genetic instruments. We conducted Mendelian randomization based on summary-level data from the International MS Genetics Consortium (47,429 cases and 68,374 controls). Reverse Mendelian randomization, Steiger filtering, Bayesian colocalization, constrained maximum likelihood, and model averaging-based (cML-MA) method, and phenomewide scanning were performed to strengthen findings. Additionally, we explored protein-protein interaction networks to uncover possible links between target proteins and approved MS therapeutics. RESULTS: Under Bonferroni significance (P < 1.52 × 10-4), Mendelian randomization using cisexpression quantitative trait locus instruments revealed nine ferroptosis-related proteins (STAT3, MAPK1, MAPK3, MAP3K11, CISD2, KEAP1, ZEB1, PVT1, PARP1) with significant results in at least one tissue. Bayesian colocalization indicated that four of them (STAT3, PP.H4=0.97; MAPK1, PP.H4=0.95; MAPK3, PP.H4=0.99; ZEB1, PP.H4=0.96) share variation with MS. Under Bonferroni significance (P < 1.11 × 10-3), two proteins also obtained significant proteomic results (STAT3, P = 1.18 × 10-13, MAPK3, P = 3.25 × 10-8). Regional association analysis and phenomewide Scanning suggest a potential involvement of STAT3 in MS. STAT3 and MAPK3 interact with target proteins of current MS drugs, particularly STAT3. DISCUSSION: These findings highlight the causal involvement of ferroptosis pathways in MS pathogenesis, emphasizing STAT3 and MAPK3 as promising therapeutic candidates. This work broadens current understanding of MS biology and suggests new directions for targeted drug development focused on ferroptosis regulation. CONCLUSION: Our analysis indicates that genetically predicted ferroptosis-related protein levels of STAT3, MAPK1, MAPK3, and ZEB1 are associated with MS risk. Among them, STAT3 and MAPK3 emerge as potential therapeutic candidates, with STAT3 warranting particular clinical investigation.