Glucocorticoids elevate clear cell renal cell carcinoma sensitivity to HIF-2α inhibitors by suppressing H4K12 lactylation

  • Signal Transduct Target Ther. 2026 Apr 1;11(1):117. doi: 10.1038/s41392-026-02622-7.
Kenan Zhang  #  1  2 ,  Lin He  #  3  4 ,  Yizhou Wang  1 ,  Sen Qin  5 ,  Chunyu Yu  6 ,  Enrun Zheng  5 ,  Zedan Zhang  1 ,  Yawei Xu  1 ,  Xiaolin Chen  1 ,  Yanhua Liu  7  5 ,  Xiaoya Liu  7  5 ,  Sudun Guan  5 ,  Lu Xia  5 ,  Feiya Suo  5 ,  Fei Pei  8 ,  Juan Du  8 ,  Yiran Su  5 ,  Yanze Li  9 ,  Yu Wu  10 ,  Xuehong Zhou  5 ,  Jingcheng Zhou  1 ,  Lin Cai  1 ,  Xinjing Tang  11 ,  Zheng Zhang  1 ,  Yongfeng Shang  12 ,  Qing Zhang  13 ,  Kan Gong  14 ,  Luyang Sun  15  16
Affiliations
  • 1. Department of Urology, Peking University First Hospital, State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
  • 2. Department of Urology, The First Hospital Affiliated to Zhengzhou University, Henan, China.
  • 3. Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking University, Beijing, China. [email protected].
  • 4. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University Health Science Center, Peking University, Beijing, China. [email protected].
  • 5. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University Health Science Center, Peking University, Beijing, China.
  • 6. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China.
  • 7. Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking University, Beijing, China.
  • 8. Department of Pathology, Peking University Health Science Center, Beijing, China.
  • 9. CapitalBio Technology Co., Ltd., Beijing, China.
  • 10. Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
  • 11. Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  • 12. National Center for Children's Health, Beijing Children's Hospital, Beijing, China.
  • 13. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 14. Department of Urology, Peking University First Hospital, State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China. [email protected].
  • 15. Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking University, Beijing, China. [email protected].
  • 16. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, Peking University Health Science Center, Peking University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41922306 DOI: 10.1038/s41392-026-02622-7
Abstract

Approximately 70% of clear cell renal cell carcinoma (ccRCC) patients harbor von Hippel‒Lindau (VHL) deficiency, which drives pseudohypoxia and metabolic reprogramming. Here, we report a histone H4 lysine 12 lactylation (H4K12la)-fueled phosphoglycerate kinase 1 (PGK1)-lactate positive feedback loop that sustains glycolytic flux in VHL-deficient ccRCC and is pharmacologically disruptable by glucocorticoids. H4K12la is markedly elevated in ccRCC tissues and is associated with advanced pathological stage and unfavorable patient outcome. Integrative transcriptomic and epigenomic profiling revealed that VHL deficiency amplifies H4K12la deposition at accessible promoters, coupled to transcriptional activation of glycolytic and tumor-promoting programs, exemplified by PGK1. Through high-content drug screening, we identify glucocorticoids as effective suppressors of H4K12la, which act via glucocorticoid receptor-mediated transcriptional repression of glycolytic genes and consequent attenuation of lactate production. Strikingly, VHL-deficient ccRCC exhibits greater on-target pathway sensitivity to dexamethasone at the H4K12la-glycolysis axis, and glucocorticoid dexamethasone potentiated the antitumor efficacy of the HIF-2α inhibitor belzutifan in both orthotopic cell line-derived and patient-derived xenograft models. Collectively, our findings establish H4K12la as a metabolic‒epigenetic amplifier in VHL-deficient ccRCC, reposition glucocorticoids as epigenetically active modulators that dampen lactate-driven chromatin activation and glycolytic output, and provide a mechanistically grounded combination strategy with HIF-2α blockade to target lactate-fueled transcriptional dependence in metabolically rigid tumors.

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