The current research revealed a strong link between lipid reprogramming and dysregulated lipid metabolism to the genesis and development of clear cell renal cell carcinoma (ccRCC). Pathologically, ccRCC exhibits a high concentration of lipid droplets within the cytoplasm. HIF-2α expression has previously been demonstrated to be elevated in ccRCC caused by mutations in the von Hippel-Lindau (VHL) gene, which plays a vital role in the development of renal cell carcinoma. Nevertheless, the mechanisms by which HIF-2α influences lipid metabolism reprogramming are unknown. Our investigation demonstrated that HIF-2α directly binds to the promoter region of LPCAT1, promoting its transcription. RNA-seq and lipidomics mass spectrometry studies showed that knocking down LPCAT1 significantly reduced triglyceride production. Research suggests that KD-LPCAT1 involves activation of the NF-κB signaling pathway, which activates F-Box/WD Repeat-Containing Protein 7 (FBXW7). FBXW7, an E3 ubiquitin ligase involved in lipid metabolism, interacts with ATP Citrate Lyase (ACLY) to promote its degradation, lowering fatty acid production and contributing to the lipid content reduction.© The author(s).