Background: Clear cell renal cell carcinoma (ccRCC) is the most prevalent and aggressive subtype of renal cell carcinoma, characterized by high recurrence rates and unfavorable prognosis. Identification of novel molecular biomarkers is crucial for improving prognostic stratification and therapeutic decision-making. Ectonucleotide pyrophosphatase/phosphodiesterase 4 (ENPP4), a member of the ENPP family, has been implicated in immune regulation and tumor biology; however, its role in ccRCC remains largely unexplored.Methods: Transcriptomic data and corresponding clinical information of ccRCC patients were obtained from The Cancer Genome Atlas (TCGA). Differential expression analyses, survival analyses, and univariate and multivariate Cox regression models were performed to evaluate the prognostic significance of ENPP4. An ENPP4-associated risk stratification model was constructed to visualize survival differences. ENPP4 expression was further validated in clinical ccRCC tissues and matched adjacent normal tissues using quantitative real-time PCR and Western blot analysis. Functional assays were conducted in ccRCC cell lines (786-O, A498, and ACHN) following shRNA-mediated ENPP4 knockdown to assess cell proliferation, migration, and invasion.Results: ENPP4 expression was significantly downregulated in ccRCC tissues compared with normal renal tissues at both the mRNA and protein levels. Low ENPP4 expression was associated with advanced tumor stage and significantly poorer overall survival. Multivariate Cox regression analysis identified ENPP4 as an independent prognostic factor in ccRCC. Risk stratification analyses further demonstrated a close association between reduced ENPP4 expression, elevated risk scores, and unfavorable survival outcomes. Functional experiments revealed that ENPP4 knockdown markedly enhanced ccRCC cell proliferation, migration, and invasion.Conclusion: Our findings indicate that ENPP4 is frequently downregulated in ccRCC and that its low expression is associated with aggressive tumor behavior and poor prognosis. ENPP4 may function as a tumor suppressor and serve as a potential prognostic biomarker, providing new insights into molecular stratification and personalized management of ccRCC.