Does redox-active iron promote lipid peroxidation and oxidative modification of LDL?

Redox-active iron is a highly reactive catalyst capable of driving cellular lipid damage and modifying circulating lipoproteins, posing a direct threat to vascular health.

Molecular mechanisms of lipid peroxidation

• Radical generation: Divalent iron ($Fe^{2+}$) in the labile iron pool drives the classical Fenton reaction with hydrogen peroxide, generating highly reactive hydroxyl radicals ($\cdot$OH).
• Propagation cascade: These radicals abstract hydrogen atoms from membrane polyunsaturated fatty acids (PUFAs), producing lipid radicals ($L^{\cdot}$) and lipid peroxyl radicals ($LOO^{\cdot}$).
• Amplification: Subsequent $Fe^{2+}$-catalyzed decomposition of lipid hydroperoxides ($LOOH$) yields aggressive alkoxyl radicals ($LO^{\cdot}$). This feedback loop leads to membrane disruption and generates toxic, non-enzymatic end-products like malondialdehyde (MDA) and $F_2$-isoprostanes.

Oxidative modification of LDL and vascular injury

• ApoB-100 modification: Redox-active iron binds directly to apolipoprotein B-100 (apoB-100) on LDL particles. Local reductants, such as superoxide or homocysteine, reduce $Fe^{3+}$ to $Fe^{2+}$, initiating localized Fenton-type chemistry.
• Atherogenic transition: This lipid peroxidation yields reactive aldehydes (MDA and 4-hydroxynonenal) that adduct apoB-100, transforming native LDL into highly atherogenic oxidized LDL (oxLDL).
• Lysosomal acceleration: This reaction is highly accelerated in acidic macrophage lysosomes (pH 4.5–5.0), where enhanced iron solubility drives rapid redox cycling.
• Endothelial ferroptosis: Accumulating oxLDL and intracellular iron synergistically deplete GPX4 and trigger ferroptosis in vascular endothelial cells, accelerating plaque progression.

Bottom line

• Redox-active iron directly promotes both systemic lipid peroxidation and the oxidative modification of LDL particles through Fenton chemistry, generating atherogenic oxLDL and driving endothelial cell death via ferroptosis.