Our study found that Nrf2, HO-1and NQO1 protein were down-regulated in renal tubules of DKD rats and HK2 cells that were exposed to high glucose; GSPE activated Nrf2/HO-1 pathway in the kidney of DKD rats and HG-stimulated renal tubular epithelial cell; and down-regulation of Nrf2 attenuated the inhibitory effect of GSPE on ferroptosis. Here, NFE2L2 is linked to diabetic kidney disease.