FTH1-mediated iron dysregulation and ferroptosis in manganese-induced neurotoxicity

Excessive environmental manganese (Mn) exposure has been implicated in neurological disorders, with iron homeostasis imbalance emerging as a crucial aspect in neurodegeneration diagnosis and therapy. However, the intricate mechanisms underlying Mn-induced neurotoxicity, particularly the interplay between ferroptosis and iron dysregulation, remain elusive. This study investigated the role of ferritin heavy chain 1 (FTH1)-mediated iron homeostasis disruption in manganese (Mn)-induced neurotoxicity and ferroptosis. Mn exposure was found to disrupt iron homeostasis and induce ferroptosis in neuronal cells by downregulating FTH1 expression. Elevated intracellular and mitochondrial Fe²⁺ and reactive oxygen species (ROS) levels, along with increased lipid peroxidation, were observed in Mn-treated Neuro-2a (N2a) cells. Notably, both deferoxamine (DFO) treatment and FTH1 overexpression alleviated iron imbalance and reduced ferroptotic markers. Our findings suggest that Mn triggers neuronal ferroptosis via FTH1-mediated oxidative stress and iron dysregulation, highlighting the potential of iron ion inhibitors or FTH1 modulation as therapeutic strategies. This study contributes to the understanding of Mn-induced neurotoxicity and provides insights into the mechanisms underlying ferroptosis in neuronal cells.