Background: Clear cell renal cell carcinoma (ccRCC) is a dominant subtype of kidney cancer with a dismal outcome at advanced stages. Ataxin 3 (ATXN3) has been proven to play a cancer-promoting role in several tumors and is upregulated in the patients with renal cell carcinoma. Thus, the objective of this research is to examine the biological roles and underlying mechanisms of ATXN3 in ccRCC. Methods: Bioinformatics analysis was carried out to analyze ATXN3 expression in ccRCC tissues and patient survival. Gain- and loss-of-function assays were applied to explore the effect of ATXN3 on ccRCC cell malignant behavior in vitro. The effect of ATXN3 on the NF-eB pathway was assessed by Western blot and immunofluorescence staining. The binding between ATXN3 and S100A8 and the effect of ATXN3 on S100A8 ubiquitination were verified using coimmunoprecipitation. Results: ATXN3 was upregulated in ccRCC tissues and correlated with adverse patient outcome. ATXN3 overexpression facilitated the proliferation, stemness, invasion and migratory capacity of ccRCC cells, whereas silencing had the opposite effect. ATXN3 enhanced the activity of the NF-eB pathway. Silencing ATXN3 facilitated S100A8 ubiquitination. Rescue experiments demonstrated that S100A8 downregulation reversed the promoting effect of ATXN3 on malignant behavior and NF-eB pathway activation in ccRCC cells. Conclusion: ATXN3 exerts a cancerpromoting effect in ccRCC by regulating S100A8 ubiquitination. Therefore, targeting the ATXN3/S100A8/ NF-eB axis may provide a novel underlying therapeutic strategy for ccRCC.  Kulcsszavak clear cell renal cell carcinoma, ATXN3, S100A8, ubiquitination, stemness, NF-eB pathway