The Iron Trap: A Hormone–Iron–Ferroptosis Framework for Sex Bias in Autoimmune, Neurodegenerative, and Cardiometabolic Diseases

The Iron Trap: A Hormone–Iron–Ferroptosis Framework for Sex Bias in Autoimmune, Neurodegenerative, and Cardiometabolic Diseases

Authors: David Millar | NeuroSynergetics | October 2025

Abstract

This pre-print manuscript proposes a novel and unifying mechanistic framework, the "Iron Trap," to explain the striking sex-dimorphic prevalence and progression observed across major chronic diseases, including autoimmunity, neurodegeneration, and cardiometabolic disorders.

Background: Iron is biologically essential, but its dysregulation accelerates oxidative stress, lipid peroxidation, and ferroptosis—an iron-dependent form of regulated cell death. Ferroptosis has emerged as a central mechanism of immune dysfunction and tissue injury. Autoimmune diseases, such as multiple sclerosis (MS), lupus, and Hashimoto’s thyroiditis, disproportionately affect women (3–4x higher prevalence), while cardiovascular risk rapidly accelerates in women post-menopause. A critical gap exists in models linking sex hormones to iron management and ferroptosis susceptibility.  

Central Hypothesis: We hypothesize that sex hormones function as essential guardians of iron homeostasis and ferroptosis resilience. The decline or suppression of these hormonal signals—through life stages like menopause or through medical interventions like hormonal contraceptives—creates the "Iron Trap," predisposing individuals to chronic inflammation and tissue collapse.  

The Iron Trap Mechanism:

The Iron Trap is driven by the failure of hormonal protection, resulting in a dual bottleneck that expands the intracellular labile iron pool (LIP), which is the redox-active fraction that catalyzes lipid peroxidation:

1. The Hepcidin Lock: Inflammation-driven elevation of hepcidin (the master iron regulator) blocks ferroportin-mediated iron export, sequestering iron within macrophages and hepatocytes.  

    

2. The HO-1 Barrier: Suppressed activity of Heme Oxygenase-1 (HO-1), often due to hormonal decline (e.g., loss of estrogen-mediated Nrf2→HO-1 activation), impairs crucial heme recycling. This not only leads to toxic heme accumulation but also reduces the production of the potent antioxidant bilirubin, eliminating a vital buffer against oxidative stress.  

    

The combined failure of the Hepcidin Lock and the HO-1 Barrier drives ferroptosis, which, in turn, fuels immune activation (skewing T-cells toward pro-inflammatory Th1/Th17 phenotypes) and initiates the oxidized LDL (oxLDL) amplification cycle, linking the Iron Trap directly to autoimmunity and cardiovascular damage.  

Novel Clinical Contribution: Iron Trap Anemia (ITA)

The framework introduces Iron Trap Anemia (ITA) as a novel, testable subtype of functional anemia. ITA is distinguished from classical Functional Iron Deficiency (FID) by its unique biomarker profile, referred to as the "Bilirubin Paradox": the coexistence of normal or high ferritin and low hemoglobin, alongside disproportionately low bilirubin. Low bilirubin, in this context, serves as a surrogate marker for the critical failure of the   .

HO-1 defense system. This distinction is critical as standard iron supplementation risks expanding the LIP and worsening ferroptotic stress in ITA patients.   

Translational Implications:

The Iron Trap framework identifies new, mechanism-based therapeutic targets focused on restoring redox homeostasis rather than merely suppressing symptoms:

• Hormonal Interventions: Hormone replacement or modulation to restore Nrf2/HO-1 activity and iron efflux.  

   

• Redox Restoration: Nrf2 activators (e.g., sulforaphane, saffron) to bolster antioxidant capacity and GPX4function   

   

• Iron Modulation: Strategies such as therapeutic phlebotomy or iron chelators (e.g., lactoferrin) to reduce the labile iron pool.  

   

• Lifestyle Interventions: Circadian/light hygiene to support endogenous HO-1 regulation.  

   

This synthesis suggests that ferroptosis may be the missing mechanistic link in autoimmunity, offering a novel path toward disease modification that addresses the root cause of chronic inflammation and tissue injury.