Lead exposure induces ferroptosis in ALS cell models by activating the MAPK/ERK signaling pathway

Lead is a potent toxicant that exerts deleterious effects on multiple organ systems within the human body. Existing evidence suggests that lead exposure may contribute to the progression of amyotrophic lateral sclerosis (ALS). However, the precise mechanism remains unclear and the experimental evidence is currently lacking. This study establishes an ALS cell model exposed to lead to investigate the potential relationship between lead exposure and ALS, and targets ferroptosis to elucidate the possible mechanism of lead exposure in ALS pathogenesis. Our findings demonstrate that lead exposure results in the accumulation of ROS and MDA in hSOD1^G93A cells, accompanied by increased iron content, reduced GSH levels, mitochondrial vacuolization, and disruption of the cristae structure, upregulationation of ACSL4 protein levels, and inactivation of SLC7A11 and GPX4, ultimately triggering ferroptosis. The bioinformatics analyses and cellular experiments of the present study suggest that activation of the MAPK/ERK signaling pathway plays a crucial role in the ferroptosis process of ALS cells induced by lead exposure. This study not only provides new experimental evidence of the link between lead exposure and ALS but also elucidates the possible mechanism by which lead exposure contributes to the pathogenesis of ALS, demonstrating that the prevention of ferroptosis through targeting the MAPK/ERK signaling pathway may offer a promising intervention strategy for addressing lead-related ALS pathogenesis issues.