Glucose-induced histone lactylation confers metformin resistance in colorectal cancer stem cells.

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.