2. Academic Validation
  3. FTH1-mediated iron dysregulation and ferroptosis in manganese-induced neurotoxicity

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

  • Neurotoxicology. 2026 Jan:112:103367. doi: 10.1016/j.neuro.2025.103367.
Xiaoli Ma 1,  Shengtao Wei 2,  Fangfei Li 2,  Guiqiang Liang 3,  Jian Wang 4,  Yunfeng Zou 5
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, China; Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning, Guangxi 530021, China; The First Affiliated Hospital of Guangxi Medical University, Guangxi Key Laboratory Base of Precision Medicine in Cardiocerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, Nanning 530021, China.
  • 2 Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, China; Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning, Guangxi 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi 530021, China.
  • 3 Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, China; Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning, Guangxi 530021, China.
  • 4 Department of Occupational and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: [email protected].
  • 5 Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, China; Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning, Guangxi 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: [email protected].
PMID: 41412472 DOI: 10.1016/j.neuro.2025.103367
Abstract

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.

Keywords

Ferroptosis; Iron homeostasis; Manganese; Neurotoxicity.

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