2. Academic Validation
  3. m6A modification of ATG9A regulates ferritinophagy in microglial activation induced by arsenic

m6A modification of ATG9A regulates ferritinophagy in microglial activation induced by arsenic

  • J Hazard Mater. 2025 Sep 15:496:139376. doi: 10.1016/j.jhazmat.2025.139376.
Tianxiu Zhou 1,  Ruiqi Zhou 1,  Xuejun Jiang 2,  Yanan Gao 1,  Jun Zhang 3,  Lixiao Zhou 1,  Wei Sun 1,  Yinyin Xia 1,  Shuqun Cheng 1,  Feng Zhao 4,  Hongyang Zhang 4,  Qian Chen 1,  Peng Su 5,  Shangcheng Xu 6,  Zhen Zou 7,  Chengzhi Chen 8
Affiliations

Affiliations

  • 1 Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China.
  • 2 Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China.
  • 3 Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China.
  • 4 Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing 400016, China.
  • 5 Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China. Electronic address: 103335@cqmu.edu.cn.
  • 6 Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China. Electronic address: xushangchengmito@163.com.
  • 7 Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China. Electronic address: zouzhen@cqmu.edu.cn.
  • 8 Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China. Electronic address: chengzhichen@cqmu.edu.cn.
PMID: 40816185 DOI: 10.1016/j.jhazmat.2025.139376
Abstract

Environmental arsenic has been extensively documented to induce neuroinflammation and various neurological disorders. Iron overload has been demonstrated to induce microglial activation, subsequently resulting in neurological dysfunction, while the precise molecular mechanisms remain to be elucidated. In this study, we demonstrated that iron chelation therapy ameliorated arsenic-induced iron overload and microglial activation, which was mediated by ferritinophagy. Upon arsenic exposure, N6-methyladenosine (m6A) modification levels were significantly elevated, corresponding to a reduction in fat mass and obesity-associated protein (FTO). Notably, both systemic and microglial-specific Fto knock-in transgenic mice demonstrated resistance to arsenic-induced microglial activation and neurological dysfunction. Conversely, systemic knock-down and conditional microglial-specific knock-out of Fto exacerbated arsenic-induced microglial activation. Through m6A-sequencing analysis, ATG9A was identified as the predominant m6A-modified autophagy-related gene in arsenic-induced ferritinophagy. The expression of ATG9A was found to be regulated by FTO in an m6A-dependent manner. Importantly, ATG9A knock-down significantly attenuated ferritin degradation in arsenic-treated microglial cells. Human cortical tissues result revealed a positive correlation between arsenic concentration and levels of iron, ATG9A, and inflammatory factors, while FTO and Ferritin levels were inversely correlated with arsenic content. These findings suggest that FTO represents a promising therapeutic target for the amelioration of arsenic-related neurotoxicity .

Keywords

Arsenic; FTO; Ferritinophagy; Iron overload; Microglial activation.

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