2. Academic Validation
  3. The Ca2+ sensor STIM1 promotes neuronal ferroptosis by regulating iron homeostasis to exacerbate brain injury after intracerebral hemorrhage

The Ca2+ sensor STIM1 promotes neuronal ferroptosis by regulating iron homeostasis to exacerbate brain injury after intracerebral hemorrhage

  • Cell Rep Med. 2026 Feb 17;7(2):102595. doi: 10.1016/j.xcrm.2026.102595.
Hongchen Zhang 1,  Lijun Ma 2,  Zheming Yue 3,  Chuanhao Lu 1,  Li Wang 1,  Min Zhang 1,  Jia Yong 1,  Yuan Feng 4,  Shiquan Wang 5,  Hongjie Wang 1,  Lu Che 1,  Yanghong Bai 6,  Weihao Lv 1,  Zhibiao Wang 7,  Liang Li 1,  Juan Wang 1,  Yang Yu 1,  Lei Zhang 1,  Qichao Huang 8,  Shuhui Dai 9,  Xia Li 10
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
  • 2 Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China; Xi'an Medical University, Xi'an 710068, China.
  • 3 Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China; 3201 Hospital, Hanzhong 723000, China.
  • 4 Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710000, China.
  • 5 Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China; Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
  • 6 Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China; Northwest University, Xi'an 710069, China.
  • 7 The Fourth Military Medical University, Xi'an 710032, China.
  • 8 Department of Physiology and Pathophysiology, The Fourth Military Medical University, Xi'an 710032, China.
  • 9 Department of Neurosurgery, Xijing 986 Hospital, The Fourth Military Medical University, Xi'an 710000, China; National Translational Science Center for Molecular Medicine and Department of Cell Biology, The Fourth Military Medical University, Xi'an 710032, China. Electronic address: daish_neuo@fmmu.edu.cn.
  • 10 Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China. Electronic address: lixia_fmmu@163.com.
PMID: 41672063 DOI: 10.1016/j.xcrm.2026.102595
Abstract

Intracerebral hemorrhage (ICH) often has a poor prognosis, necessitating the exploration of effective therapeutic targets. Stromal interaction molecule 1 (STIM1) is a crucial regulator of cellular calcium homeostasis, but its specific role in ICH remains unclear. This study finds consistent elevation of STIM1 in neurons after ICH, with increased plasma levels in patients correlating with poor prognosis. Neuronal knockout of STIM1 in mice improves brain tissue damage and neurological injury. Mechanistically, STIM1 exacerbates neuronal injury primarily by promoting Ferroptosis. Importantly, in addition to regulating calcium signaling pathways, STIM1 directly regulates iron homeostasis through its interaction with Transferrin Receptor 1 (TFR1) to promote Ferroptosis. Finally, through virtual screening, S-IN-1 is identified as an inhibitor targeting STIM1-TFR1 interaction, protecting against neuronal Ferroptosis and brain injury. These findings confirm the molecular function of STIM1 in regulating iron homeostasis, providing valuable insights and promising targets for ICH treatment.

Keywords

STIM1; TFR1; ferroptosis; intracerebral hemorrhage; iron homeostasis; neuron.

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