Embelin Mitigates the Impact of Perinatal Inflammation on Neuron Development by Inhibiting 5‐Lipoxygenase‐Mediated Ferroptosis

ABSTRACT Neuronal development in newborns is often constrained by perinatal inflammation, with limited research available on the pathogenesis and treatment strategies for this condition. This study aimed to investigate the neuroprotective effects of Embelin in mitigating perinatal inflammation‐induced neuronal development limitations by targeting 5‐lipoxygenase (5‐LOX) and reducing oxidative stress and ferroptosis. This study utilized in vivo and in vitro inflammation models to assess the therapeutic potential of Embelin, a small molecule drug from the FDA compound library. Using Autodock software and surface plasmon resonance detection technology, 5‐LOX was identified as the molecular target of Embelin. Neuronal ferroptosis and oxidative stress were analyzed in rat models and PC12 cells treated with lipopolysaccharide (LPS) and Embelin. Biochemical assays, immunofluorescence staining, and western blotting were performed to quantify protein expression and oxidative stress markers. Embelin, along with the 5‐LOX inhibitor Zileuton and 5‐LOX mRNA silencing, significantly inhibited 5‐LOX expression in neurons. Conversely, overexpressed 5‐LOX promoted ferroptosis, and this effect could be inhibited by Embelin. These interventions reduced oxidative stress, suppressed ferroptosis, and promoted normal neuronal development in the cerebral cortex and hippocampus. The findings highlight Embelin's ability to specifically target and mitigate 5‐LOX‐induced ferroptosis, facilitating recovery from perinatal inflammation‐induced neurodevelopmental deficits. Embelin demonstrates significant neuroprotective potential by inhibiting 5‐LOX‐mediated ferroptosis and oxidative stress, offering a promising therapeutic strategy for perinatal brain injury and related neurodevelopmental disorders.