2. Academic Validation
  3. The effect and mechanism of NCOA4-mediated ferritinophagy in aluminum-induced ferroptosis of PC12 cells

The effect and mechanism of NCOA4-mediated ferritinophagy in aluminum-induced ferroptosis of PC12 cells

  • Food Chem Toxicol. 2025 Aug 13:205:115699. doi: 10.1016/j.fct.2025.115699.
Ruifeng Liang 1,  Jiafen Zhang 2,  Yan Luo 2,  Yizhe Yang 2,  Ting Zhou 2,  Siyi Li 2,  Jiawei Liu 2,  Bingbing Zhang 2,  Qiao Niu 3,  Hongmei Zhang 2,  Xiaojiang Qin 2,  Junhong Gao 4
Affiliations

Affiliations

  • 1 Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China; MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Shanxi, China; Research Center for Ecologica1Public Health and Safety in the Yellow River Basin, Shanxi Medical University, Taiyuan, Shanxi, China. Electronic address: liangruifengsy@163.com.
  • 2 Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China.
  • 3 Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China; Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, Shanxi, China.
  • 4 Toxicology Research Center, CNGC Institute of Industrial Health, Xi'an, 710065, China.
PMID: 40816462 DOI: 10.1016/j.fct.2025.115699
Abstract

Aluminum (Al) can accumulate in the brain and cause significant neurotoxicity, with neuronal death being a major contributor to aluminum-induced cognitive decline. Recent studies highlight the involvement of Nuclear Receptor Coactivator 4 (NCOA4)-mediated ferritinophagy and Ferroptosis in this process, but their specific roles remain unclear. In this study, PC12 cells were treated with aluminum maltolate [Al(mal)3], with or without deferoxamine (DFO), a Ferroptosis inhibitor, to explore the role of Ferroptosis in aluminum-induced toxicity. Ferritinophagy was further examined using 3-Methyladenine (3-MA) and small interfering RNA (siRNA) targeting NCOA4. Al(mal)3 treatment increased intracellular iron, Reactive Oxygen Species (ROS), and malondialdehyde (MDA) levels, while reducing glutathione (GSH), mitochondrial membrane potential (MMP), and Glutathione Peroxidase 4 (GPX4) expression-hallmarks of Ferroptosis. DFO and inhibition of ferritinophagy reversed these effects. Moreover, suppression of NCOA4 restored ferritin levels and improved iron homeostasis. These findings suggest that aluminum may activate NCOA4-mediated ferritinophagy, leading to disrupted iron metabolism, oxidative stress, and Ferroptosis in neuronal cells, thereby contributing to its neurotoxic effects.

Keywords

Aluminium; Ferritinophagy; Ferroptosis; Neuron; Neurotoxicity; PC12 cells.

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