The association of iron overload with cerebrovascular disease and cognitive impairment has been reported in b-thalassemia patients. However, the mechanism of iron overload leading to cerebrovascular pathology is still unclear. This study aimed to investigate the effects of iron overload on blood-brain barrier (BBB) damage contributing to brain pathology leading to cognitive impairment in b-thalassemia mice (BKO) as a disease model. This study can enhance the understanding of the pathophysiology of iron overload-related cognitive impairment in b-thalassemia, including mechanistic insight into iron overload and brain pathology specifically in BBB alteration. This study provides a foundation for further research into the neuroprotective effects of iron chelation therapy and other interventions aimed at preserving BBB integrity and neuronal health, thereby improving the quality of life for b-thalassemia patients.