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A critical safety consideration is metformin-associated lactic acidosis (MALA), which is extremely rare but serious
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Further extending this paradigm, the reverse Warburg effect describes a stromal-epithelial coupling where cancer-associated fibroblasts (CAFs), under oxidative stress, activate hypoxia-inducible factor 1-alpha (HIF-1) and release lactate via MCT4, which cancer cells then import via MCT1 to fuel their oxidative metabolism, creating an acidic, lactate-rich niche that supports tumor growth [59]
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