Diabetes mellitus (DM) is a common metabolic disease of aging around the world, leading to many chronic complications, including cardiovascular disease, peripheral neuropathy, and diabetic retinopathy. Epidemiological studies have documented an association between diabetes and an increased risk of cognitive decline in the elderly (Bellia et al., 2022). People with type 2 diabetes mellitus (T2DM) show poorer cognitive performance, with a certain degree of reduction in memory, processing speed, and executive function (Alkethiri et al., 2021; Pugazhenthi et al., 2017). The mechanisms underlying diabetic cognitive impairments are complicated and involve impaired insulin signaling, inflammation, and oxidative stress. A recent study revealed iron overload in the hippocampus of db/db mice (An et al., 2022).

Ferroptosis, a form of regulated cell death characterized by the accumulation of intracellular iron and lipid peroxidation, was first proposed by Dixon et al. in 2012 (Dixon et al., 2012). It is different from apoptosis, necrosis, and autophagy in morphology, biochemistry, and genetics. Morphologically, ferroptotic cell death produces smaller, crumpled and broken mitochondria, while other forms of cell death often manifest as mitochondrial swelling (Alkethiri et al., 2021). Inhibition of glutathione peroxidase 4 (GPX4), a phospholipid peroxidase, causes lethal accumulation of lipid peroxides and triggers ferroptosis (Seibt et al., 2019). Small molecules (e.g., erastin and Ras selective lethal 3 are widely adopted for the induction of ferroptosis. A lipid peroxidation inhibitor, such as ferrostatin 1 (Fer-1), can inhibit the occurrence of ferroptosis (Dixon et al., 2012).

Iron homeostasis plays an important role in the central nervous system (CNS) and is essential for brain health and development. Iron deficiency has negative effects on psychomotor and cognitive functions in children (Vallée, 2017). Iron accumulation in brain regions is associated with neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease (AD), and Huntington's disease (HD) (Yu and Chang, 2019). Brain iron accumulation may be accompanied by oxidative stress, inflammation, and cell death. Iron deposition was observed in both the hippocampal CA1 area and the cerebral cortex in a chronic cerebral hypoperfusion rat model (Li et al., 2012). A growing body of evidence suggests that the activation of ferroptosis is associated with neurodegenerative diseases, such as AD and HD (Ashraf and So, 2020; Skouta et al., 2014). Moreover, ferroptosis is associated with diabetic cognitive dysfunction, and solute carrier family 40 member 1 (SLC40A1, ferroportin-1), which transports iron into cells, mediates ferroptosis in a streptozotocin (STZ)-induced type 1 diabetes mellitus rat model (Hao et al., 2021). Considering that excess iron accumulation is associated with many neurodegenerative diseases and induces the production of reactive oxygen species (ROS) in the brain, ferroptosis is likely involved in T2DM-associated cognitive dysfunction.

Erythropoietin (EPO), a 30.4-kDa glycoprotein composed of 165 amino acids, promotes the production of red blood cells. Several studies have reported that EPO exhibits anti-apoptotic, anti-inflammatory, antioxidant, and neuroprotective effects. EPO alleviates oxygen and glucose deprivation-induced cortical neuronal apoptosis in a dose-dependent manner (Si et al., 2019). In addition, EPO treatment significantly decreases the infiltration and activation of immune/inflammatory cells, including neutrophils, CD3+ T cells, and microglia, in the fluid percussion injury mouse model (Zhou et al., 2017). A previous study reported that EPO protects hippocampal neurons from lipid peroxidation and oxidative stress-induced damage in young rats (Al-Qahtani et al., 2014). Xiong et al. reported that EPO plays an important role in synaptogenesis and neurite repair (Xiong et al., 2019). In addition, EPO regulates iron metabolism and induces shifts in the iron pool, which may ameliorate excess free iron and iron accumulation (Boesch and Indelicato, 2019). According to previous research, EPO can improve iron overload and lipid peroxidation to produce neuroprotective effects. Therefore, we aimed to explore whether EPO ameliorates T2DM-associated cognitive dysfunction by inhibiting iron-dependent fatal lipid peroxidation-induced ferroptosis.