Do higher iron stores increase oxidative stress and sustain low-grade inflammation?

Molecular mechanisms of iron-catalyzed oxidative stress

Under physiological conditions, systemic iron is tightly bound to transferrin and intracellular iron is safely sequestered within the 24-subunit shell of ferritin, preventing it from participating in deleterious redox reactions. However, when iron stores are elevated—reflected by high serum iron and ferritin—the normal buffering capacity of ferritin is saturated.

• Labile iron pool expansion: Excess intracellular iron overflows into the cytosol and mitochondria, significantly expanding the labile iron pool (LIP), consisting of redox-active, chelatable divalent iron ($\text{Fe}^{2+}$).
• Fenton and Haber-Weiss chemistry: This free, redox-active divalent iron acts as a potent catalyst. Through Fenton chemistry, $\text{Fe}^{2+}$ reacts with hydrogen peroxide ($\text{H}_2\text{O}_2$) to generate highly destructive hydroxyl radicals ($\cdot\text{OH}$).
• Superoxide amplification: This reaction is continuously fueled by Haber-Weiss chemistry, where superoxide radicals ($\text{O}_2^{\bullet-}$) reduce oxidized trivalent iron ($\text{Fe}^{3+}$) back into its reactive divalent form ($\text{Fe}^{2+}$), perpetuating a relentless cycle of reactive oxygen species (ROS) generation.
• Macromolecular damage: These iron-catalyzed ROS directly attack cellular lipids, proteins, and DNA, resulting in marked lipid peroxidation (evidenced by elevated malondialdehyde and F2-isoprostanes) and mitochondrial dysfunction.

Mechanistic links to chronic inflammation

The accumulation of iron-catalyzed ROS does not remain localized; it acts as an upstream trigger for chronic, systemic low-grade inflammation.

• Pro-inflammatory signaling cascade: Elevated intracellular ROS function as critical second messengers that activate the I$\kappa$B kinase (IKK) complex, prompting the nuclear translocation of the master transcription factor NF-$\kappa$B.
• Inflammasome priming: Concurrently, these reactive oxygen species prime and activate the NLRP3 inflammasome.
• Cytokine and biomarker elevation: Once activated, the NF-$\kappa$B and NLRP3 pathways drive the transcription, maturation, and secretion of key pro-inflammatory cytokines, including tumor necrosis factor-alpha ($\text{TNF}-\alpha$), interleukin-1 beta ($\text{IL}-1\beta$), and interleukin-6 ($\text{IL}-6$). In turn, circulating $\text{IL}-6$ stimulates hepatocytes to synthesize and release high-sensitivity C-reactive protein (hs-CRP), a clinical hallmark of systemic inflammation.
• Ferroptotic amplification: Severe, unchecked lipid peroxidation from excess iron can also trigger ferroptosis, a form of non-programmed cell death. The resulting cellular rupture releases damage-associated molecular patterns (DAMPs) and lipid oxidation products that activate surrounding macrophages, further sustaining a localized and systemic inflammatory state.

Bottom line

Higher iron stores, reflected by elevated ferritin and iron, expand the redox-active labile iron pool to drive hydroxyl radical generation via Fenton/Haber-Weiss chemistry. These reactive oxygen species trigger the NF-$\kappa$B and NLRP3 inflammasome pathways, elevating systemic cytokines ($\text{IL}-6$, $\text{TNF}-\alpha$) and hs-CRP, thereby sustaining chronic low-grade inflammation.