Clinical and preclinical interest in Type 2 diabetes (T2D)-associated cognitive dysfunction (TDACD) has grown in recent years. However, the precise mechanisms underlying TDACD need to be further elucidated. Ferroptosis was reportedly involved in neurodegenerative diseases and diabetes-related organ injuries; however, its role in TDACD remains elusive. In this study, mice fed with a high-fat-diet combined with streptozotocin (HFD-STZ) were used as a T2D model to assess the role of ferroptosis in cognitive dysfunction. We found that ferroptosis was mainly activated in hippocampal neurons but not in microglia or astrocytes. Accordingly, increased levels of transferrin receptor and decreased levels of ferritin, GPX4, and SLC7A11 were observed in hippocampal neurons. In addition, pre-treatment with liproxstatin-1, a ferroptosis inhibitor, attenuated iron accumulation and oxidative stress response, which resulted in improved cognitive function in the HFD-STZ group. Furthermore, we found that p-AMP-activated protein kinase (AMPK) was decreased in the HFD-STZ group. Pre-treatment with AMPK agonist increased the expression of AMPK and GPX4, but decreased lipocalin 2 (LCN2) in the hippocampus that resulted in improved spatial learning ability in the HFD-STZ group. Taken together, we found that activation of neuronal ferroptosis in the hippocampus contributed to cognitive impairment of HFD-STZ mice. Furthermore, AMPK activation may reduce hippocampal ferroptosis, and consequently improve cognitive performance in diabetic mice.Copyright © 2022 Elsevier Inc. All rights reserved.