Elovl7 sensitizes podocytes to ferroptosis in podocytopathy by elongating polyunsaturated fatty acids

Abstract Podocytopathy is an emerging global health concern characterized by the injury of podocytes through various direct or indirect mechanisms. Recent research has highlighted a potential link between podocyte loss and various programmed cell death pathways, while the precise mechanisms of podocyte injury remain ambiguous. We conducted single-nucleus RNA sequencing (snRNA-seq) on kidney tissues from adriamycin-induced nephropathy (AN) mice (BALB/c, male) and renal biopsy samples from patients with different types of podocytopathy, such as focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD) and obesity-related glomerulopathy (ORG). We found podocytes in diseased groups exhibited elevated ferroptosis scores based on the gene module score of programmed cell death pathways. Targeted lipidomics analysis revealed high phospholipids (PLs) levels containing long-chain polyunsaturated fatty acyl (LC-PUFA) tails. Metabolic pathway activity analysis indicated dysregulation of fatty acid elongation in podocytes of the AN group. We further reveal that the upregulation of Elovl7 in injured podocytes led to the accumulation of PLs with LC-PUFA tails, resulting in heightened sensitivity to ferroptosis. The results were confirmed by podocyte specific Elovl7 knockout mice and Elovl7 knockdown podocyte cell line. In conclusion, our study visualized injured podocytes and substantial podocyte loss from multiple podocytopathies. This phenomenon could potentially be attributed to the increased synthesis of LC-PUFAs facilitated by Elovl7, which leads to accumulation of intracellular lipid peroxidation and ultimately leading to ferroptosis.