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Dual Metabolic Inhibition by Berberine and Glutor Triggers AMPK/JNK-Dependent DNA Damage in Cancer Cells

Meina Shi1,2, Chengming Wei3, Dayuan Zheng1,2

  • 1State Key Laboratory of Mechanism and Quality of Chinese Medicine & Faculty of Chinese Medicine, Macau University of Science and Technology, Macau SAR, 999078, China.

International Journal of Medical Sciences
|June 22, 2026
PubMed

Insights

Combining berberine (BBR) and Glutor, a dual metabolic inhibitor, synergistically kills cancer cells by blocking glucose uptake and mitochondrial function. This dual inhibition triggers metabolic stress, activating the AMPK/JNK pathway, leading to apoptosis.

Area of Science:

  • Oncology
  • Metabolic Pathways
  • Cancer Therapeutics

Background:

  • Metabolic reprogramming is crucial for tumor survival and therapeutic resistance.
  • Targeting single metabolic pathways often fails due to tumor adaptability.
  • Berberine (BBR) inhibits mitochondrial complex I, while Glutor inhibits multiple glucose transporters.

Purpose of the Study:

  • To investigate the synergistic antitumor activity of combining BBR and Glutor.
  • To elucidate the underlying molecular mechanisms of the combination therapy.
  • To evaluate the efficacy of dual metabolic inhibition in cancer models.

Main Methods:

  • In vitro antiproliferative assays on HeLa, HepG2, and HCT116 cancer cell lines.
  • Measurement of cellular ATP levels, glycolysis, and oxidative phosphorylation (OXPHOS).
  • Analysis of AMPK and JNK signaling pathway activation, DNA damage, and homologous recombination repair (HRR).
  • Ex vivo studies using tumor explant models.

Main Results:

  • The BBR and Glutor combination demonstrated significant synergistic antiproliferative effects.
  • Co-administration suppressed both glycolysis and OXPHOS, leading to ATP depletion and AMPK activation.
  • Metabolic stress activated the JNK pathway, causing DNA damage and impairing HRR, ultimately inducing apoptosis.
  • JNK inhibition attenuated DNA damage and partially restored HRR proteins.
  • The combination therapy showed cooperative antitumor activity in ex vivo tumor explants.

Conclusions:

  • Simultaneous inhibition of glucose uptake/glycolysis and OXPHOS (dual metabolic inhibition) effectively impairs cancer cell survival.
  • The AMPK/JNK signaling axis is a critical mediator of the antitumor effects induced by dual metabolic inhibition.
  • This combination strategy offers a promising approach for overcoming therapeutic resistance in cancer.
Keywords:
ATPBerberineDNA damageGlutorJNK

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