〔Abstract〕 Objective To explore the effect of astilbin(astilbin-CS-NPs)-loaded chitosan nanoparticles(CS-NPs) on high glucose(HG)-induced ferroptosis of renal tubular epithelial cellsviaregulating mitogen-activated protein kinase 14(MAPK14)/heat shock protein 27(HSP27). Methods HK-2 cells were divided into the following groups: normal glucose(NG) group, HG group, HG+astilbin-CS-NPs(0, 5, 10, 20 mg/L) group, and under HG condition, pcDNA3.1-MAPK14 group, pcDNA3.1-MAPK14+astilbin-CS-NP group, si-HSP27 group, pcDNA3.1-MAPK14+si-HSP27 group, and pcDNA3.1-MAPK14+si-HSP27+astilbin-CS-NPs group. Cell viability was detected using CCK-8 assay, cell apoptosis was detectedviaTunel assay. Meanwhile, iron ion levels, lactate dehydrogenase(LDH) activity, glutathione(GSH) levels, and reactive oxygen species(ROS) levels were measured using assay kits. Rat model of diabetic kidney disease(DKD) was constructed and intervened with astilbin-CS-NPs to explore the effects of astilbin-CS-NPs on DKDin vivo. Results Compared with the NG group, the HK-2 cell viability in the HG group was significantly reduced, apoptosis increased, iron ion levels, LDH activity, and ROS levels were significantly elevated, while GSH levels significantly decreased(allP<0.05). Treatment with astilbin-CS-NPs significantly reversed the effects of HG on the biological behavior of HK-2 cells and ferroptosis-related indicators. Additionally, compared to the pcDNA3.1 group, the pcDNA3.1-MAPK14 group showed increased ferroptosis, which was improved by knocking down HSP27 or co-intervention with astilbin-CS-NPs.In vivoexperimental results showed that astilbin-CS-NPs could improve DKD rat kidney injury, inhibit iron ion levels and the expression of MAPK14/HSP27. Conclusion Astilbin-CS-NPs may improve HG-induced ferroptosis of renal tubular epithelial cellsviainhibition of MAPK14 and HSP27 expression.