Slc22a17 governs postnatal neurogenesis by maintaining the iron homeostasis in hippocampus

  • Nat Commun. 2025 Dec 15;16(1):11117. doi: 10.1038/s41467-025-66108-w.
Lei Tao  #  1 ,  Long Teng  #  1 ,  Mengmeng Ge  #  1  2 ,  Yaqi Wang  #  1 ,  Chengliang Hu  1 ,  Jianan Chen  1 ,  Jingyu Zhao  1 ,  Lili Cheng  1 ,  Zijuan Zhang  1 ,  Wei Qin  1 ,  Yichang Jia  3 ,  Da Mi  2  3 ,  Zengqiang Yuan  4 ,  Ligong Chen  5  6
Affiliations
  • 1. State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, China.
  • 2. School of Life Sciences, Tsinghua University, Beijing, China.
  • 3. DG/McGovern Institute for Brain Research at Tsinghua University, Beijing, China.
  • 4. The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China.
  • 5. State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, China. [email protected].
  • 6. State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Innovation Center of Basic Research for Metabolic-Associated Fatty Liver Disease, Ministry of Education of China, Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. [email protected].
  • # Contributed equally.
PMID: 41397957 DOI: 10.1038/s41467-025-66108-w
Abstract

Iron transporters are essential for numerous iron-dependent biological processes. Among them, SLC22A17 plays a key role in lipocalin-2 (LCN2)-mediated iron transport and is implicated in several human diseases. However, its precise molecular and physiological functions remain poorly understood. In this study, we demonstrate that Slc22a17 is critical for postnatal neurogenesis through its regulation of iron homeostasis in the hippocampus. Conditional knockout of Slc22a17 in the murine brain results in early postnatal mortality, severe growth retardation, excessive neural stem cell (NSC) Apoptosis, and cognitive impairments, all driven by oxidative stress caused by iron overload. Mechanistically, using TurboID-based proximity labeling and immunoprecipitation, we identify an interaction between Slc22a17 and p62, which modulates Nrf2 activity. Loss of Slc22a17 activates the Nrf2/HO-1 pathway, paradoxically enhancing iron release while impairing iron efflux. This imbalance triggers the production of iron-catalyzed Reactive Oxygen Species (ROS), leading to oxidative stress. Together, our findings highlight Slc22a17 as a potential therapeutic target for neurological disorders associated with iron dysregulation.

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