Si-Tao Chen, Duan-Rui Zhou, Yun-Jun Ge, Lei Chang, Shu-Hui Guo, Guo-Sheng Wu, Ninghan Feng
Background: Clear cell renal cell carcinoma (ccRCC or KIRC) is a malignant neoplasm characterized by reprogrammed lipid metabolism. Fatty acid desaturase 3 (FADS3), a sphingoid Δ14Z desaturase, is required for the synthesis of unsaturated fatty acids in tumor biology. However, the role of FADS3 in ccRCC progression and prognosis and in modulating the tumor immune microenvironment (TIME) remains to be elucidated. Methods: The ccRCC transcriptomic datasets were obtained from the TCGA, GEO, and GTEx databases. Mendelian randomization (MR) and single-cell RNA sequencing analyses were used to investigate the associations of FADS3 with lipid metabolism, and differential expression genes in ccRCC. Bioinformatics analysis was also used to investigate the association of FADS3 expression with tumor progression, prognosis, TIME, and potential pathogenic mechanism in ccRCC. FADS3 expression in ccRCC cell lines was confirmed by qRT-PCR, western blotting, RNA-Seq. FADS3 roles in ccRCC were assessed by functional assays including cell proliferation, migration, invasion, and colony formation using wild-type and FADS3-knockdown cell lines. Results: Lipid metabolism was found to be upregulated in ccRCC tumor tissues based on comprehensive bioinformatic analysis. FADS3 was among the upregulated genes associated with lipid metabolism, which was expressed not only in ccRCC tumor cells but also in cells of the TIME, such as tumor-associated macrophages (TAMs). High FADS3 expression remodeled the TIME and predicted poor prognosis in ccRCC. Functional assays demonstrated that FADS3 knockdown markedly suppressed ccRCC cell proliferation, migration and invasion. Transcriptomic analyses further suggested that FADS3 may promote ccRCC progression through activation of oncogenic and metabolic signaling pathways, such as the PI3K/Akt pathway. Conclusion: FADS3 is a lipid metabolism-associated oncogenic driver in ccRCC, and its upregulation remodels the TIME and predicts poor prognosis. FADS3 may represent a potential therapeutic target for ccRCC treatment.