CLCN5 inhibits tumorigenesis and fatty acid accumulation in clear cell renal cell carcinoma by regulating Enoyl CoA hydratase and 3-Hydroxyacyl CoA dehydrogenase.

Clear cell renal cell carcinoma (ccRCC), a globally prevalent and highly aggressive malignancy, is characterized by abnormal lipid accumulation and high morbidity. However, the complex pathological mechanisms underlying its development remain largely unexplored, necessitating further research efforts. In this study, we employed Weighted Gene Co-expression Network Analysis (WGCNA) and identified Chloride Voltage-Gated Channel 5 (CLCN5), a member of the CIC family, as a potential hub gene involved in fatty acid degradation. Our findings suggest that downregulated CLCN5 was negatively correlated with the malignant characteristics and prognosis of ccRCC. In vitro experiments demonstrated that CLCN5 overexpression significantly impacts fatty acid oxidation and inhibits tumor proliferation, metastasis, migration, and invasion in ccRCC. Mechanistically, CLCN5 restrains the proliferation and migration of ccRCC cells by decreasing lipid accumulation through the effects of Enoyl CoA hydratase and 3-Hydroxyacyl CoA dehydrogenase (EHHADH). Collectively, these findings suggest that CLCN5/EHHADH-mediated fatty acid metabolism could be a potential strategy for ccRCC treatment.