Metformin and valproic acid combo strips cancer cells of chemo tolerance

Chemotherapy rarely kills every cancer cell in a tumor. A small fraction survives treatment by entering a slow-growing, stress-resistant state known as drug tolerance, and these drug-tolerant persister cells, or DTPs, are widely suspected of seeding relapse after patients initially respond to therapy. A new study from researchers led by Sanjay Gupta, published in the journal Cancer & Metabolism, reports that these surviving cells depend on a specific metabolic rewiring — and that the rewiring itself can be turned against them.

The work builds on the group’s earlier finding that pre-sensitizing cancer cells with a histone deacetylase, or HDAC, inhibitor before treatment with the chemotherapy drug cisplatin significantly reduces the formation of persister cells. But the researchers recognized a problem: even when DTP formation is reduced, the persister cells that do survive may still drive tumor relapse through additional adaptive mechanisms. The new study set out to identify what those mechanisms are in gastric and liver carcinoma cell lines.

Using transmission electron microscopy, immunoblotting, metabolic assays and in vivo xenograft experiments, the team characterized the metabolic and mitochondrial adaptations that allow DTPs to persist. The persister cells showed increased levels of MFN1 and MFN2, proteins that mediate mitochondrial fusion, alongside activation of the PGC-1α/NRF2/TFAM axis, a signaling pathway that drives mitochondrial biogenesis — the production of new mitochondria. Together, these changes pointed to enhanced oxidative phosphorylation, the process by which mitochondria generate cellular energy.

That metabolic shift came with functional consequences. The persister cells produced more ATP, the cell’s energy currency, and mounted stronger antioxidant survival responses, helping them withstand the oxidative and drug-induced stress of chemotherapy. In other words, the cells that escape cisplatin do not simply lie dormant; they actively rebuild their energy machinery to endure.

The therapeutic idea followed directly from this observation. If persister cells depend on mitochondrial respiration, then attacking that dependency should leave them vulnerable. The researchers tested a combination of two widely used drugs at low doses: valproic acid, a class I HDAC inhibitor that alters epigenetic gene regulation, and metformin, a diabetes drug that inhibits mitochondrial complex I and suppresses oxidative phosphorylation. Cancer cells were pre-sensitized with the pair before receiving cisplatin.

The strategy worked in the laboratory models. Low-dose pre-sensitization with valproic acid and metformin followed by cisplatin significantly enhanced cell death in the drug-tolerant persister cells, according to the study. The combination appears to strike at two levels simultaneously — the epigenetic state that supports tolerance and the mitochondrial metabolism that sustains it.

The team then moved to an animal model.

Analysis of tumor tissue from the treated mice revealed molecular signatures consistent with the intended mechanism. The researchers observed increased H3K9 acetylation, an epigenetic mark reflecting HDAC inhibition; reduced Ki67, a marker of cell proliferation; altered AMPK levels, consistent with the metabolic disruption expected from metformin; and elevated caspase-3 expression, indicating that the cancer cells were undergoing apoptosis, or programmed cell death.

The authors are careful about the scope of their conclusions. The findings, they write, provide initial evidence for a clinically relevant strategy to inhibit or delay tumor relapse — evidence drawn from carcinoma cell lines and a mouse xenograft model rather than from human trials.

By mapping how persister cells rewire their mitochondria to survive, and by showing that a low-dose drug pair can strip away that survival advantage before cisplatin is delivered, the researchers offer a template for attacking the cells that conventional treatment leaves behind. Whether the same strategy holds in patients with gastric and liver cancer will depend on the trials that must now follow.

Subject of Research: Metabolic and epigenetic reprogramming of drug-tolerant persister cells in gastric and liver cancer

Article Title: Metabolic-epigenetic reprogramming with low-dose metformin and valproic acid sensitizes drug-tolerant persister cells to cisplatin in gastric and liver cancer

Article References: Singh, A., Natu, A., Anthony, F., Lunibo, C. S., Karkhanis, A., Khade, B., Smoot, D. T., Ashktorab, H., & Gupta, S. (2026). Metabolic-epigenetic reprogramming with low-dose metformin and valproic acid sensitizes drug-tolerant persister cells to cisplatin in gastric and liver cancer. Cancer & Metabolism. https://doi.org/10.1186/s40170-026-00455-0

Image Credits: AI Generated

DOI: 10.1186/s40170-026-00455-0

Keywords: drug-tolerant persister cells, chemoresistance, metformin, valproic acid, cisplatin, mitochondrial biogenesis, HDAC inhibitor, gastric cancer, liver cancer, xenograft model, epigenetics, Cancer & Metabolism