AIM: To explore the therapeutic effect and possible molecular mechanisms of prednisone combined with icariin (ICA) on hormone resistant nephrotic syndrome (SRNS). METHODS: In the in vivo experiment, rats were divided into control group, SRNS group, prednisone group, and P+I group. Each group was given corresponding drugs for 6 weeks. Detection of 24-hour urinary protein in rats using CBB; The blood biochemistry analyzer detects rat albumin, total cholesterol, triglycerides, creatinine, and urea nitrogen; HE and Masson were used to detect morphological changes in rat kidney tissue; Immunohistochemical detection of GR-α, GR-β, NLRP3, caspase-1, GSDMD, IL-1β. In the in vitro experiment, HK-2 cell injury model with doxorubicin, divided into control group, SRNS group, prednisone group, P+I group. GR-α, GR-β, NLRP3, caspase-1, GSDMD were detected by Rt-PCR and Western blot. RESULTS: In the in vivo experiment, compared with the control group, the SRNS group showed weight loss, increased 24-hour urine protein, decreased albumin, increased total cholesterol, triglycerides, creatinine, and urea nitrogen, renal tubular atrophy, increased renal interstitial area, significant infiltration of inflammatory cells, fibrous tissue proliferation, and GR-β, NLRP3, caspase-1, GSDMD, IL-1 β in renal tissue decreased (P<0.01); Compared with the SRNS group, the combined group showed weight gain, decreased 24-hour urine protein, increased albumin, decreased total cholesterol, triglycerides, creatinine, and urea nitrogen, reduced renal tubular atrophy, reduced interstitial inflammatory cell infiltration, reduced fibrosis, and and GR-α,NLRP3,caspase-1,GSDMD in renal tissue decreased increased (P<0.01). In vitro experiments, compared with the control group, the model group showed GR-β, NLRP3, caspase-1, and GSDMD increased (P<0.01), GR-α decreased (P<0.01); Compared with the SRNS group, GR- β, NLRP3, caspase-1, and GSDMD decreased (P<0.01), GR-α increased in the P+I group. CONCLUSION: The combination of prednisone and ICA has a protective effect on the kidneys of SRNS rats and can improve the therapeutic effect. The mechanism may be related to the NLRP3/Caspase-1/GSDMD pathway.