Proteomic Mapping of Hippocampal Pathways Involved in Lead (Pb)–Induced Neurotoxicity

ABSTRACT Lead (Pb) is a well‐known xenobiotic and neurotoxin. Chronic Pb exposure remains a major public health concern, particularly in developing countries, and is associated with cognitive impairment, memory deficits, and peripheral and central nervous system toxicity. Pb readily crosses the blood–brain barrier by competing with iron for transport via divalent metal transporter 1 and mimicking calcium to enter through Ca‐permeable ion channels, thereby disrupting Fe homeostasis and blood–brain barrier integrity. Pb accumulation promotes excessive generation of reactive oxygen species, mitochondrial dysfunction, lipid peroxidation, and neuroinflammatory responses in the brain. These events alter apoptotic signaling pathways, impair Ca‐dependent neuronal communication, and disrupt cholinergic neurotransmission, leading to synaptic dysfunction and neuronal loss in the hippocampus. Proteomic studies have provided insights into the molecular mechanisms underlying Pb‐induced neurotoxicity by identifying various Pb‐interacting proteins involved in metal transport, oxidative stress regulation, apoptosis, synaptic plasticity, and neurotransmitter signaling. In the absence of effective pharmaceutical treatments for Pb poisoning, these proteomic insights highlight potential diagnostic biomarkers and therapeutic targets that play a central role in antioxidant defense and inflammation control. Emerging enzymatic biosensors also offer promising tools for the rapid and sensitive detection of Pb exposure. Collectively, this review integrates mechanistic, proteomic, and translational perspectives to understand Pb‐induced neurotoxicity and support the development of improved diagnostic and mitigation strategies for Pb exposure.