Fer-1 improves cognitive dysfunction in chronic kidney disease through the Sirt2/PGC-1α signaling pathway based on RNA sequencing.

Ferroptosis is a non-apoptotic form of cell death characterized by cellular accumulation of iron-dependent lipid peroxidation. In recent years, a series of studies have proved that ferroptosis participate in the progression of chronic kidney disease (CKD). Notably, cognitive dysfunction is commonly found in CKD patients and it has been recognized as one of CKD pathological features. However, the character of ferroptosis in CKD related cognitive dysfunction remains unclear. This study aims to verify if ferroptosis participates in the CKD related cognitive dysfunction and the underlying mechanism. Then we use Fer-1 and Erastin to explore the effects of ferroptosis on cognition changes in CKD rat. RNA-seq analysis identified ferroptosis related lipid metabolism was significantly changed in CKD rats and the DEGs played an important role in oligodendrocyte differentiation, which were correlated with cognition ability. Fer-1 ameliorated the ultrastructure of hippocampal CA1 region and rescued the myelin sheath injury in CKD rats. Specifically, Fer-1 increased the density of myelinated axons and upregulated the levels of MBP and SOX10 in hippocampus of CKD rats. Notably, Fer-1 decreased the expression of Sirt2 and the AAV-Sirt2 abrogated the beneficial effects of Fer-1 on ferroptosis and myelin sheath in the hippocampus of CKD rats. This study provides a new strategy for improving cognitive dysfunction in CKD.