Ferroptosis: Reinterpreting Cardiovascular Disease Through the Lens of the Iron Trap Hypothesis

This preprint introduces the Iron Trap Hypothesis (ITH) as a novel systems biology framework that redefines cardiovascular disease (CVD) as a ferroptosis-mediated redox collapse, fundamentally challenging the cholesterol-centric paradigm. Integrating long-standing anomalies (e.g., the cardioprotective effects of blood donation, post-menopausal risk surges) with recent advances in redox biology, the paper traces the central role of iron overload, mitochondrial dysfunction, and environmental stressors such as blue light, EMFs, PUFAs, and toxins in disrupting the HO-1/Nrf2 axis.

A Bayesian model comparison across 25 observations yields a 96.1% posterior probability in favor of the ITH, far surpassing competing models (lipid, inflammation, autoimmune, oxidative stress). The hypothesis is further supported by comorbidity clustering across iron-rich organs (e.g., 30–50% overlap with neurodegeneration, NAFLD, and diabetes), highlighting a systemic ferroptotic signature.

The paper proposes a novel biomarker panel and targeted interventions such as phlebotomy, HO-1 agonists, circadian restoration, and nutritional strategies to interrupt the ferroptotic cascade and restore redox coherence.

Appendices include: historical figures and discoveries (e.g., Ott, Sullivan), clinical reference ranges, dietary analyses, and comorbidity tables, providing a detailed roadmap for future translational research and clinical trials.

This work aims to catalyze a paradigm shift toward redox-centered precision cardiology, and is released open access to foster global collaboration, critique, and refinement.