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Metabolism, Diabetes, and Cancer / Cancer, Lipids, and Metabolism / Cancer, Hypoxia, and Metabolism · Journal article
Nature Communications · September 7, 2026
Raises a question worth testing. It does not answer one.
This is a mechanistic study demonstrating that high glucose promotes metformin resistance in colorectal cancer stem cells via a lactate–histone lactylation–CD36 axis that shifts metabolism toward lipid oxidation. The work proposes LDHA and CD36 inhibition as potential strategies to restore metformin sensitivity, but provides no human clinical data and does not establish clinical efficacy or safety of the proposed interventions.
In vitro and in vivo mechanistic study. CD133⁺ colorectal cancer stem cells (CSCs) cultured in vitro and in vivo; specific origin, passage, or culture conditions not stated.. Intervention: High glucose conditions; metformin treatment; inhibition of LDHA or CD36.. Compared with: Standard glucose conditions; no inhibitor control implied but not explicitly stated..
High glucose conditions promote metformin resistance in CD133⁺ colorectal CSCs by driving a metabolic switch from glucose dependence to lipid use. Metformin increases LDHA-dependent lactate production; lactate accumulation enhances histone H3 lysine 18 lactylation (H3K18la), which activates c-JUN and induces CD36 expression. CD36 promotes free fatty acid uptake and lipid droplet formation, generating ATP and NADPH, reducing energy stress and reactive oxygen species, and supporting CSC survival during metformin treatment.
LDHA and CD36 inhibitors proposed as targets but no efficacy, safety, or pharmacokinetic data for these combinations provided.
This work identifies a potential metabolic escape mechanism for metformin resistance in a subpopulation of colorectal cancer cells. Clinicians should note that no patient data, clinical trials, or validated combination regimens are presented; the findings are preclinical and require validation before translation to therapeutic use.
A mechanistic study identifying a metabolic pathway and proposing drug targets, but without clinical efficacy data, human trials, or validation of the proposed combination therapy.
As stated by the source record.
Quoted from the source exactly as published.
This work identifies a potential metabolic escape mechanism for metformin resistance in a subpopulation of colorectal cancer cells. Clinicians should note that no patient data, clinical trials, or validated combination regimens are presented; the findings are preclinical and require validation before translation to therapeutic use.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Abstract Cancer stem cells (CSCs) can adapt their metabolism, which limits the effectiveness of therapies targeting metabolic pathways. Here we show that high glucose conditions promote metformin resistance in CD133⁺ colorectal CSCs by driving a switch from glucose dependence to lipid use. Mechanistically, metformin increases LDHA-dependent lactate production in these cells under high glucose conditions. Lactate accumulation enhances histone H3 lysine 18 lactylation (H3K18la), which activates c-JUN and induces CD36 expression. CD36 promotes free fatty acid (FFA) uptake and lipid droplet (LD) formation, providing fuel for fatty acid β-oxidation. This process generates ATP and NADPH, reduces energy stress and reactive oxygen species, and thereby supports CSC survival during metformin treatment. In vitro and in vivo, inhibition of either LDHA or CD36 restores metformin sensitivity in CD133⁺ colorectal CSCs. These findings identify a lactate-driven epigenetic and metabolic pathway underlying metformin resistance and suggest LDHA and CD36 as potential therapeutic targets.
Taken from the source record, never inferred. Follow any of these and new work involving them reaches your briefing.