<p>Salidroside (SAL) is a drug supplement with cytoprotective properties that can relieve the effects of diabetes-related complications. This study aims to investigate the function of SAL in diabetic nephropathy (DN). The expression of related genes and proteins was detected by RT-qPCR, western blot, immunofluorescence and immunohistochemistry. Cell proliferation and apoptosis were detected by CCK-8 and TUNEL. HE, Masson and PAS staining were used to evaluate the pathological changes of kidney in DN rats. The results showed that SAL suppressed miR-21-5p expression by upregulating lncRNA ZEB1-AS1(ZEB1-AS1) and thus promoting PDCD4 expression, inhibiting cell apoptosis, promoting podocyte proliferation and migration, and alleviating podocyte injury in DN. Further in vivo experiments demonstrated that SAL-treated rats exhibited decreases in blood urine nitrogen (BUN) and the urine albumin–creatinine ratio (ACR), and SAL ameliorated the severity of DN, while knocking down ZEB1-AS1 weakened the effect of SAL. Our data suggested that the upregulation of ZEB1-AS1 by SAL participated in the ceRNA network and had a key function in alleviating DN podocyte injury through ZEB1-AS1-miR-21-5p-PDCD4 crosstalk. In conclusion, this study demonstrated that SAL inhibited DN podocyte injury through the ZEB1-AS1/miR-21-5p/PDCD4 axis.</p> Graphic Abstract <p></p>