Related Experiment Video

Updated: Aug 6, 2026

Site-Specific Lysine Lactylation via Genetic Code Expansion in E. coli and Mammalian Cells
05:58

Site-Specific Lysine Lactylation via Genetic Code Expansion in E. coli and Mammalian Cells

Published on: February 24, 2026

AARS1-catalyzed H4K12 lactylation promotes HCC resistance to targeted therapy by activating RAPGEF3-RAP1 signaling

Tanlun Zeng1,2, Wanwan Zhu1, Guanqun Sun1

  • 1Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, China.

Cell Death & Disease
|July 21, 2026
PubMed

Insights

Histone lactylation, driven by lactate, promotes targeted drug resistance in liver cancer by activating the AARS1-H4K12la-RAPGEF3 pathway. Targeting this axis may improve treatment outcomes for hepatocellular carcinoma (HCC) patients.

Area of Science:

  • Oncology
  • Metabolic pathways
  • Epigenetics

Background:

  • Hepatocellular carcinoma (HCC) is a glycolytic malignancy with limited response to current targeted therapies like sorafenib and lenvatinib.
  • The role of histone lactylation in driving resistance to these therapies in HCC remains largely unknown.
  • Understanding resistance mechanisms is crucial for improving patient survival rates.

Purpose of the Study:

  • To investigate the role of histone lactylation in mediating resistance to receptor tyrosine kinase inhibitors in HCC.
  • To identify the molecular pathways involved in lactate-induced drug resistance.
  • To explore potential therapeutic targets for overcoming targeted therapy resistance in HCC.

Main Methods:

  • Clinical cohort analysis to correlate histone lactylation levels with patient prognosis and drug resistance.
  • Biochemical assays to determine the enzymatic regulation of histone lactylation by lactate.
  • CUT&Tag and ATAC-seq to identify downstream targets of histone lactylation.
  • In vitro and in vivo experiments using drug inhibitors and HCC models.

Main Results:

  • Increased nuclear pan-lysine lactylation (pan-Kla) and H4K12la levels are associated with poor HCC prognosis and targeted drug resistance.
  • Lactate regulates H4K12la via AARS1 (writer) and HDAC11 (eraser) enzymes.
  • H4K12la activates RAPGEF3, a key regulator of the RAP1 signaling pathway, thereby conferring drug resistance.
  • Inhibiting RAPGEF3 or combining a RAPGEF3 inhibitor with lenvatinib synergistically suppressed HCC growth.

Conclusions:

  • A novel metabolic-epigenetic mechanism links lactate, histone lactylation (H4K12la), and targeted drug resistance in HCC via the AARS1-H4K12la-RAPGEF3 axis.
  • The AARS1/H4K12la/RAPGEF3 axis is a potential therapeutic target to overcome sorafenib resistance in HCC.
  • Targeting this pathway offers a promising strategy to enhance clinical outcomes for HCC patients.

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