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<p>Subarachnoid hemorrhage (SAH) is a devastating stroke subtype often leading to poor neurological outcomes. Iron homeostasis imbalance is a key contributor to cognitive dysfunction in neurological diseases. Extracellular vesicles, including exosomes (EXs), are crucial mediators of intercellular communication. This study investigated the role of EXs in post-SAH iron metabolism and neurological impairment. We isolated EXs from various neural cells (microglia, astrocytes, endothelial cells, neurons; <i>n</i> = 4–6 independent isolations) in vitro after SAH mimicked by oxyhemoglobin (OxyHb) or hemin. We found that microglial EXs (MC-EXs) were significantly enriched in iron and potently impaired neuronal viability. Using specific inhibitors and fluorescence imaging, we demonstrated that neurons internalize MC-EXs primarily via dynamin-dependent, clathrin-, caveolae-, and lipid raft-mediated endocytosis. Combining transcriptomic analysis with in vivo and in vitro SAH models, we discovered that iron-overloaded MC-EXs induce neuronal ferroptosis. In mice, intranasal administration of MC-EXs (10⁹ particles/day for 3 days, <i>n</i> = 10/group) exacerbated SAH-induced motor, sensory, and cognitive deficits. Bioinformatic analysis and experimental validation (including C3 siRNA knockdown) identified the complement C3/C5/NF-κB pathway as a key molecular mechanism through which iron-overloaded MC-EXs trigger ferroptosis. This research provides evidence for a novel EX-mediated mechanism for iron toxicity in SAH, highlighting MC-EXs and the C3/C5/NF-κB axis as potential therapeutic targets.</p> Graphical Abstract <p></p>

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Microglia-derived iron-overloaded exosomes induce neuronal ferroptosis and aggravate neurological impairment after subarachnoid hemorrhage

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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  • Yuchen Li,
  • Bowen Sun,
  • Zurong Yao,
  • Xinqiao Li,
  • Harshal Sawant,
  • Le Huang,
  • Xi-Ao Wang,
  • Pei Wu,
  • Fanchao Meng,
  • Jiuling Chen,
  • Huaizhang Shi,
  • Ji Bihl

摘要

Subarachnoid hemorrhage (SAH) is a devastating stroke subtype often leading to poor neurological outcomes. Iron homeostasis imbalance is a key contributor to cognitive dysfunction in neurological diseases. Extracellular vesicles, including exosomes (EXs), are crucial mediators of intercellular communication. This study investigated the role of EXs in post-SAH iron metabolism and neurological impairment. We isolated EXs from various neural cells (microglia, astrocytes, endothelial cells, neurons; n = 4–6 independent isolations) in vitro after SAH mimicked by oxyhemoglobin (OxyHb) or hemin. We found that microglial EXs (MC-EXs) were significantly enriched in iron and potently impaired neuronal viability. Using specific inhibitors and fluorescence imaging, we demonstrated that neurons internalize MC-EXs primarily via dynamin-dependent, clathrin-, caveolae-, and lipid raft-mediated endocytosis. Combining transcriptomic analysis with in vivo and in vitro SAH models, we discovered that iron-overloaded MC-EXs induce neuronal ferroptosis. In mice, intranasal administration of MC-EXs (10⁹ particles/day for 3 days, n = 10/group) exacerbated SAH-induced motor, sensory, and cognitive deficits. Bioinformatic analysis and experimental validation (including C3 siRNA knockdown) identified the complement C3/C5/NF-κB pathway as a key molecular mechanism through which iron-overloaded MC-EXs trigger ferroptosis. This research provides evidence for a novel EX-mediated mechanism for iron toxicity in SAH, highlighting MC-EXs and the C3/C5/NF-κB axis as potential therapeutic targets.

Graphical Abstract