Unveiling the impact of ferroptosis on diabetes‐associated cognitive decline through comprehensive single‐cell RNA sequencing and experimental studies

Diabetes-associated cognitive decline (DACD) is defined as an impairment of cognitive functions, including memory, attention and executive functions, attributed to chronic hyperglycemia and metabolic dysregulation associated with type 2 diabetes mellitus (T2DM). Ferroptosis is a regulated form of cell death that is dependent on iron and is primarily characterized by the excessive accumulation of lipid peroxides within cellular membranes, and also plays a critical role by exacerbating neuronal loss and synaptic dysfunction. The present study aims to use single-cell RNA sequencing (scRNA-seq) technology to investigate the role of ferroptosis in microglia and oligodendrocytes in DACD, thereby elucidating the pathogenesis of DACD. scRNA-seq and bulk RNA-seq datasets were analyzed for differential gene expression in hippocampus samples of T2DM and control mice, with an emphasis on oligodendrocytes and microglia cell types. We further constructed a T2DM model in mice and conducted behavioral analyses to evaluate cognitive functions. Additionally, we explored the role of ferroptosis in the progression of DACD disease by knocking down transferrin receptor 1 (Tfr1) using small interfering RNA and utilizing the ferroptosis inhibitor ferrostatin-1. The study identified significant alterations in the expression of ferroptosis-related genes Fth1, Slc40a1, Slc3a2, Trf, Tfrc and Sat1 in T2DM mice, suggesting the possible involvement of ferroptosis in DACD. Knocking down Tfr1 and inhibiting ferroptosis could significantly alleviate inflammation and oxidative stress damage in oligodendrocytes. This research provides new perspectives into the pathophysiology of DACD, emphasizing the critical role of ferroptosis and offering a potential therapeutic target to mitigate neurological damage and cognitive impairment associated with T2DM.