Prolonged exposure to environmental levels of microcystin-LR triggers ferroptosis in brain via the activation of Erk/MAPK signaling pathway.

While existing research has illuminated the environmental dangers and neurotoxic effects of MC-LR exposure, the molecular underpinnings of brain damage from environmentally-relevant MC-LR exposure remain elusive. Employing a comprehensive approach involving RNA sequencing, histopathological examination, and biochemical analyses, we discovered genes differentially expressed and enriched in the ferroptosis pathway. This finding was associated with mitochondrial structural impairment and downregulation of Gpx4 and Slc7a11 in mice brains subjected to low-dose MC-LR over 180 days. Mirroring these findings, we noted reduced cell viability and GSH/GSSH ratio, along with an increased ROS level, in HT-22, BV-2, and bEnd.3 cells following MC-LR exposure. Intriguingly, MC-LR also amplified phospho-Erk levels in both in vivo and in vitro settings, and the effects were mitigated by treatment with PD98059, an Erk inhibitor. Taken together, our findings implicate the activation of the Erk/MAPK signaling pathway in MC-LR-induced ferroptosis, shedding valuable light on the neurotoxic mechanisms of MC-LR. These insights could guide future strategies to prevent MC-induced neurodegenerative diseases.