2. Academic Validation
  3. FUT8 reprograms glycolytic metabolism to promote PKM2 lactylation and drive clear cell renal cell carcinoma progression

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

  • Cell Death Discov. 2026 Mar 19;12(1):146. doi: 10.1038/s41420-026-03013-1.
Zikai Guo # 1 2,  Hongxiao Jiang # 2 3,  Xu Wang # 4,  Ke Xuan 2,  Huidong Zhong 5,  Chengxi Liu 6,  Mengkai Zhang 2,  Zhichao Li 7,  Weiren Huang 8 9 10 11 12,  Yangyang Sun 13
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 2 The First Affiliated Hospital, Shenzhen University; Shenzhen Second People's Hospital; Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, Shenzhen, China.
  • 3 Guangxi University of Chinese Medicine, Nanning, China.
  • 4 The Third Affiliated Hospital of Anhui Medical University (The First People's Hospital of Hefei), Hefei, China.
  • 5 Department of Oncology, Ji'an Central Hospital, Ji'an, China.
  • 6 Department of Applied Biology and Chemical Technology, Food Safety and Technology Research Centre, and Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
  • 7 The First Affiliated Hospital, Shenzhen University; Shenzhen Second People's Hospital; Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, Shenzhen, China. [email protected].
  • 8 Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. [email protected].
  • 9 The First Affiliated Hospital, Shenzhen University; Shenzhen Second People's Hospital; Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, Shenzhen, China. [email protected].
  • 10 State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. [email protected].
  • 11 Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, China. [email protected].
  • 12 GuangDong Engineering Technology Research Center for Clinical Application Of Cancer Genome, Shenzhen, China. [email protected].
  • 13 State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. [email protected].
  • # Contributed equally.
PMID: 41857011 DOI: 10.1038/s41420-026-03013-1
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.

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