Manganese stimulates ferroptosis to trigger neurotoxicity in mice and HT22 cells: the role of NCOA4-mediated ferritinophagy

Manganese (Mn), an essential trace element for physiological functions, can induce neurotoxicity through iron-dependent oxidative stress mechanisms when present in excess. This study reveals that Mn triggers ferroptosis in neural cells via nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Using in vivo (Mn-exposed mice) and in vitro (hippocampal HT22 cells) models, we demonstrated that Mn exposure disrupts iron homeostasis, elevating brain iron accumulation and downregulating ferroptosis-protective proteins (SLC7A11 and GPX4). The ferroptosis inhibitor ferrostatin-1 effectively counteracted Mn-induced cell death, whereas the extracellular iron chelator deferoxamine showed limited protection. Crucially, NCOA4 knockdown significantly mitigated Mn-induced iron overload and cell viability loss, outperforming deferoxamine. These findings establish ferritinophagy as a central mechanism in Mn neurotoxicity and highlight the therapeutic potential of targeting intracellular iron regulation over extracellular chelation. Our work provides a mechanistic foundation for developing interventions against Mn-associated neurodegenerative disorders. © 2025 Elsevier B.V., All rights reserved.