Clear cell renal cell carcinoma (ccRCC) represents the predominant and remarkably diverse form of renal cell carcinoma. The involvement of the Castor zinc finger 1 (CASZ1) gene in adverse prognostic outcomes has been observed across different cancer types. Nevertheless, the specific altered activities and associated multi-omics characteristics of CASZ1 in ccRCC remain unelucidated.In order to explore the expression of CASZ1, evaluate its prognostic significance, and aid in the therapeutic decision-making process for patients with ccRCC, the The Cancer Genome Atlas(TCGA), Gene expression omnibus (GEO), and The Human Protein Atlas (HPA) databases were utilized to gather data on clinicopathological data, prognostic information, genomic, methylomic and immunomic data. Additionally, the Genomics of drug sensitivity in cancer (GDSC) database provided information on drug sensitivity.CASZ1 expression was found to be significantly reduced in ccRCC and was associated with unfavorable pathological characteristics and a bleak prognosis. Diminished CASZ1 mRNA levels were notably correlated with heightened cytosine-phosphate-guanine (CpG) methylation , indicating a poorer prognosis for patients with increased methylation. Examination of RNA-seq data from TCGA indicated that the CASZ1-high expression subgroup displayed heightened immune cell infiltration and increased expression of immune checkpoint markers, potentially suggesting a more favorable response to immunotherapy. Furthermore, data from the GDSC database indicated that the CASZ1-low expression subgroup might exhibit greater sensitivity to anti-angiogenetic treatments, such as Sunitinib and Axitinib.These results indicate that CASZ1 may function as a biomarker for distinguishing various tumor microenvironment phenotypes, predicting prognosis, and assisting in treatment decisions for individuals with ccRCC.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.