Epigenetically-controlled CEBPB regulates kidney cancer tumorigenesis via GPD1L-mediated ether lipid synthesis

Clear cell renal cell carcinoma (ccRCC) is characterized by disrupted lipid metabolism, traditionally attributed to VHL mutations and HIF stabilization. Here, we identified CEBPB as an epigenetically upregulated, VHL-independent transcription factor driving ccRCC tumorigenesis. CEBPB was regulated by H3K27ac and H3K4me and transcriptionally repressed the tumor-suppressive glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), thereby elevating dihydroxyacetone phosphate (DHAP)-derived ether lipid synthesis and enhancing Akt signaling. This activation suppressed CPT1A expression, inhibiting fatty acid oxidation (FAO) and leading to lipid accumulation, as found by lipidomics and isotope tracing. Loss of CEBPB reduced ether lipids, reactivated CPT1A, and impaired Akt signaling, diminishing tumor growth and lipid content in vitro and in vivo. Restoration of ether lipids or Akt activity rescued these effects. Importantly, CEBPB expression and enhancer activation were not modulated by VHL status and it could be targeted pharmacologically. The CEBPB-GPD1L-ether lipid-Akt-CPT1A axis is proposed as a new druggable driver in ccRCC integrating epigenetics, transcription, intermediary metabolism and oncogenic signaling.