The Iron Trap Hypothesis for Multiple Sclerosis: A Bayesian Evaluation Against Leading Theories of Disease Pathogenesis

This paper introduces the Iron Trap Hypothesis, a novel and integrative model for the pathogenesis of multiple sclerosis (MS), reframing it as a systemic iron-driven neurodegenerative disorder. Through a Bayesian comparative analysis of eight leading MS models, the Iron Trap Hypothesis achieved a posterior probability of ~90.7%, surpassing the next-best model by over 23-fold under consistent assumptions. It posits that suppression of the Nrf2–heme oxygenase-1 (HO-1) pathway triggered by environmental factors (e.g., low sunlight, toxins), hormonal changes (e.g., estrogen decline), infections (e.g., Epstein–Barr virus), and lifestyle stressors (e.g., smoking, circadian disruption), impairs heme breakdown, leading to redox-active iron accumulation, ferroptosis, and progressive damage to myelin-producing cells and iron-rich organs (e.g., liver, heart, optic nerves). The hypothesis uniquely explains early iron deposition on susceptibility-weighted imaging (SWI/QSM) before demyelination, progression without inflammatory relapses, systemic comorbidities, and biochemical signatures like elevated ferritin and lipid peroxidation markers (4-HNE, MDA). It highlights a critical measurement gap in MS diagnostics: standard MRI protocols often omit iron-sensitive SWI/QSM, and ferroptosis-related biomarkers (e.g., ferritin, transferrin saturation, GPX4 activity) are rarely assessed, perpetuating the oversight of iron’s role. The paper proposes falsifiable predictions across imaging, biomarkers, lifestyle patterns, and therapeutic responses, advocating for updated diagnostics (SWI/QSM, ferroptosis panels) and interventions (HO-1 inducers, iron chelators, lifestyle modifications) to target root causes. Designed to inspire rigorous validation, this work calls for interdisciplinary collaboration to reshape MS research and care, offering a roadmap for transformative diagnostics and therapies.