Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN

  • Cell Death Dis. 2025 Jan 31;16(1):59. doi: 10.1038/s41419-025-07359-9.
Yuan Zeng  #  1 ,  Haoran Jiang  #  2  3 ,  Zhoufeng Chen  1 ,  Jun Xu  1 ,  Xiangting Zhang  1 ,  Weimin Cai  1 ,  Xianjie Zeng  4 ,  Peipei Ma  1 ,  Rong Lin  1 ,  Huilin Yu  5 ,  Yuanhang He  5 ,  Huiya Ying  1 ,  Ruoru Zhou  1 ,  Xiao Wu  6 ,  Fujun Yu  7
Affiliations
  • 1. Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2. Department of Radiation Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3. Department of Urology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4. School of Pharmaceutical Science, Fujian Medical University, Fujian, China.
  • 5. The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 6. Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • 7. Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 39890782 DOI: 10.1038/s41419-025-07359-9
Abstract

FOLFOX (5-fluorouracil, oxaliplatin, folinic acid) is a standard treatment for hepatocellular carcinoma, but its efficacy is often limited by drug resistance, the underlying mechanisms of which remain unclear. In this study, oxaliplatin (OXA)- and 5-fluorouracil (5-Fu)-resistant hepatocellular carcinoma cell lines were established, and enhanced glycolytic activity was identified in resistant cells. Inhibiting glycolysis effectively suppressed the malignant behavior of both OXA- and 5-Fu-resistant cells. Mechanistically, active glycolysis induced elevated levels of lactylation, predominantly histone lactylation, with H3K14la playing a key role in regulating gene expression. The ubiquitin E3 Ligase NEDD4 was identified as a downstream target of H3K14la. Furthermore, NEDD4, regulated by histone lactylation, interacted with PTEN to mediate its ubiquitination and subsequent degradation. The downregulation of PTEN formed a positive feedback loop, further driving the malignant progression of OXA- and 5-Fu-resistant cells. This study elucidates a shared mechanism underlying OXA and 5-Fu resistance in hepatocellular carcinoma and highlights a promising therapeutic target for overcoming clinical chemotherapy resistance.

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