Molecular Basis of Ferroptosis and Pyroptosis in Lead-Induced Neurotoxicity: A Narrative Review of Current Evidence and Therapeutic Implications.

Abstract

Lead (Pb) is a well-established potent neurotoxicant. Biochemically, overexposure to Pb is associated with alterations in synaptic signaling and neurotransmission, causing disruptions in neuronal activity and hence resulting in the manifestation of developmental-related disorders. Furthermore, lead-induced neurotoxicity triggers ferroptosis and pyroptosis through mechanical pathways, including oxidative stress, mitochondrial dysfunction, and neuroinflammatory signaling. Recently, the inhibition of ferroptosis and pyroptosis has been explored as a potential treatment strategy against neurodegenerative diseases. However, a comprehensive synthesis of the molecular mechanisms linking these regulated cell death pathways to Pb-induced neurotoxicity is lacking. This narrative review synthesizes the current evidence on how Pb may influence key regulators of ferroptosis and pyroptosis, including the dysregulation of iron homeostasis, inhibition of the antioxidant system, excess reactive oxygen species generation (ROS), lipid peroxidation, and NLRP3/caspase-1-mediated cleavage and gasdermin D-dependent release of proinflammatory cytokines. In addition, this review integrates the current understanding of the potential crosstalk between ferroptosis and pyroptosis, identifies critical knowledge gaps and discusses emerging therapeutic interventions targeting these regulated cell death pathways. Although the literature provides experimental links between exposure to Pb and non-apoptotic -regulated cell death, including ferroptosis and pyroptosis, across in vivo and in vitro models, studies underlying its molecular mechanisms are lacking. Hence, in-depth investigations and evaluations are necessary to provide a framework for exploring the convergence of these pathways in lead neurotoxicity, as well as for the development of therapeutic strategies against Pb-induced ferroptosis and pyroptosis in neurodegeneration.