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.