Glycidol induces ferroptosis via the Nrf2/GPX4 pathway disrupting the blood-brain barrier and impairing neurological homeostasis

Glycidol (GLD) is a common hazardous contaminant generated during thermal food processing, with well-documented genotoxicity and potential carcinogenicity. GLD is found in many processed foods, such as milk powder, potato chips, and coffee, as a result of the degradation of glyceryl esters (GEs) during heating. In this study, a Balb/c mouse model was used to evaluate the effects of GLD at different doses on neural homeostasis. Exposure to GLD led to reduced weight gain and metabolic disorders in mice. Behavioral assessments further revealed impairments in spatial learning and memory, as well as motor coordination. The in vitro cell model demonstrated that GLD significantly altered the expression of ferroptosis-specific proteins (Nrf2, GPX4, ACSL4), leading to the accumulation of reactive oxygen species (ROS), the inhibition of antioxidant enzyme (SOD, CAT, GSH) activity, and the increase in the level of malondialdehyde (MDA). In addition, GLD induced ferroptosis in brain tissue by inhibiting the Nrf2/GPX4 pathway, disrupting the expression of tight junction proteins (ZO-1, occludin), which in turn increased blood-brain barrier (BBB) permeability. Concurrently, GLD exposure elevated the release of inflammatory factors such as TNF-α and IL-6. Collectively, this study reveals a new mechanism by which GLD impairs BBB function and induces neurobehavioral disorders through ferroptosis, oxidative stress, and neuroinflammation, providing a new avenue for assessing the neurotoxicity by food processing byproducts.