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<p>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 <i>Slc22a17</i> 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 <i>Slc22a17</i> 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.</p>

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Slc22a17 governs postnatal neurogenesis by maintaining the iron homeostasis in hippocampus

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月15日

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  • Lei Tao,
  • Long Teng,
  • Mengmeng Ge,
  • Yaqi Wang,
  • Chengliang Hu,
  • Jianan Chen,
  • Jingyu Zhao,
  • Lili Cheng,
  • Zijuan Zhang,
  • Wei Qin,
  • Yichang Jia,
  • Da Mi,
  • Zengqiang Yuan,
  • Ligong Chen

摘要

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.