2. Academic Validation
  3. Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN

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

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. wuxiao@wmu.edu.cn.
  • 7 Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. yufujun@wmu.edu.cn.
  • # 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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