This study investigates the role of iron accumulation in the hippocampus following intracerebral hemorrhage (ICH) and its impact on cognitive impairment. Key findings include: 1. **Iron Accumulation and Cognitive Impairment**: Clinical and animal studies show that iron accumulation in the hippocampus, away from the site of ICH, is associated with cognitive impairment. Susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM) techniques revealed significant iron accumulation in the hippocampus of ICH patients, which correlated negatively with cognitive function. 2. **Neural Stem Cell (NSC) Overactivation and Depletion**: In a mouse model of ICH, iron accumulation triggers excessive activation of NSCs, leading to their overactivation and subsequent depletion. This results in diminished neurogenesis and progressive cognitive dysfunction. 3. **Mechanistic Insights**: Iron accumulation increases reactive oxygen species (ROS) levels, which downregulate the expression of Itga3. Pharmacological chelation of iron or scavenging of ROS, along with conditional overexpression of Itga3 in NSCs, significantly mitigates NSC pool exhaustion, abnormal neurogenesis, and cognitive decline. 4. **RNA Sequencing and Gene Expression Analysis**: RNA sequencing identified Itga3 as a key gene involved in the process of NSC pool exhaustion after ICH. Overexpression of Itga3 in NSCs rescued the negative effects of iron accumulation on NSC activation and neurogenesis. 5. **Behavioral Tests**: Behavioral assessments, including the Morris water maze, novel object recognition, and new object location tests, confirmed the cognitive impairment in ICH mice and the beneficial effects of iron chelation and ROS scavenging. These findings provide molecular insights into the mechanisms underlying ICH-induced cognitive impairment and highlight the potential therapeutic targets for preventing cognitive dysfunction in patients with hemorrhagic stroke.This study investigates the role of iron accumulation in the hippocampus following intracerebral hemorrhage (ICH) and its impact on cognitive impairment. Key findings include: 1. **Iron Accumulation and Cognitive Impairment**: Clinical and animal studies show that iron accumulation in the hippocampus, away from the site of ICH, is associated with cognitive impairment. Susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM) techniques revealed significant iron accumulation in the hippocampus of ICH patients, which correlated negatively with cognitive function. 2. **Neural Stem Cell (NSC) Overactivation and Depletion**: In a mouse model of ICH, iron accumulation triggers excessive activation of NSCs, leading to their overactivation and subsequent depletion. This results in diminished neurogenesis and progressive cognitive dysfunction. 3. **Mechanistic Insights**: Iron accumulation increases reactive oxygen species (ROS) levels, which downregulate the expression of Itga3. Pharmacological chelation of iron or scavenging of ROS, along with conditional overexpression of Itga3 in NSCs, significantly mitigates NSC pool exhaustion, abnormal neurogenesis, and cognitive decline. 4. **RNA Sequencing and Gene Expression Analysis**: RNA sequencing identified Itga3 as a key gene involved in the process of NSC pool exhaustion after ICH. Overexpression of Itga3 in NSCs rescued the negative effects of iron accumulation on NSC activation and neurogenesis. 5. **Behavioral Tests**: Behavioral assessments, including the Morris water maze, novel object recognition, and new object location tests, confirmed the cognitive impairment in ICH mice and the beneficial effects of iron chelation and ROS scavenging. These findings provide molecular insights into the mechanisms underlying ICH-induced cognitive impairment and highlight the potential therapeutic targets for preventing cognitive dysfunction in patients with hemorrhagic stroke.