Lactoferrin as a therapeutic modulator of oxidative stress in inflammatory conditions

Oxidative stress, driven by excess reactive oxygen species (ROS), induces widespread biomolecular damage through the oxidation of lipids, proteins, and nucleic acids, contributing to the onset and progression of numerous inflammatory diseases. Among these, 4-hydroxynonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) are widely recognized as biomarkers of lipid peroxidation and oxidative DNA damage, respectively. In this study, we have investigated the potential of lactoferrin, an innate immune glycoprotein with established antioxidant and anti-inflammatory properties, to modulate the activity of these reactive byproducts. Using molecular dynamics simulations, fluorescence quenching, and surface plasmon resonance (SPR) assays, we describe the molecular basis of lactoferrin's interactions with 4-HNE and 8-OHdG. Lactoferrin demonstrated micromolar binding affinities toward both ligands, with fluorescence and SPR data revealing direct interactions. Structural analysis suggests that the flexible interdomain interface of lactoferrin facilitates binding, enabling effective sequestration of lipid-derived ROS byproduct, and its C-lobe facilitates binding to oxidative bases. These findings advance our understanding of lactoferrin's molecular mechanism of redox modulation and support its therapeutic. This study positions lactoferrin as a multifunctional modulator of oxidative stress with relevance across diverse inflammatory pathologies.