FUT8 reprograms glycolytic metabolism to promote PKM2 lactylation and drive clear cell renal cell carcinoma progression

Abstract Clear cell renal cell carcinoma (ccRCC) is characterized by the loss of the von Hippel–Lindau (VHL) gene, leading to constitutive activation of hypoxia-inducible transcription factors (HIFs) and metabolic reprogramming toward aerobic glycolysis. Although core fucosylation catalysed by fucosyltransferase 8 (FUT8) is known to regulate receptor signaling and tumor malignancy, its role in metabolic regulation of ccRCC remains poorly defined. Here, we demonstrate that FUT8 knockdown significantly suppresses ccRCC proliferation and migration both in vitro and in vivo. Mechanistically, FUT8 enhances HIF-1α–driven glycolysis, increasing lactate production and promoting pan-lysine lactylation (pan-Kla). Specifically, FUT8 promotes pyruvate kinase M2 (PKM2) K115 lactylation, which boosts its enzymatic activity while reducing nuclear localization, thereby driving epithelial–mesenchymal transition and malignant progression. Collectively, our findings reveal the FUT8–HIF-1α–lactate–PKM2 axis as a key mechanism that links core fucosylation to metabolic reprogramming and malignant progression in ccRCC and highlights FUT8 as a promising therapeutic target.