AMPK as a Double-Edged sword in cancer: role of natural compounds in its regulation

AMPK is a central cellular energy sensor that maintains metabolic homeostasis by coordinating anabolic and catabolic processes. AMPK acts as a double-edged regulator in cancer: it enforces metabolic growth suppression or promotes stress adaptation and therapeutic resistance, depending on specific context factors including tumour genotype, nutrient supply and oxygenation, disease stage, therapeutic exposure, and microenvironmental cues. Natural compounds, including flavonoids, stilbenes, alkaloids, and terpenoids, have been shown to modulate AMPK activity through upstream regulators such as LKB1 and CaMKK, often via mitochondrial stress. SAR studies highlight how chemical features such as hydroxylation and prenylation influence AMPK activation and downstream signalling. Despite encouraging anticancer evidence, challenges remain, including dose-dependent effects, limited bioavailability, and intratumoral heterogeneity. This review discusses the complex role of AMPK in cancer, the modulatory effects of natural compounds, and strategies to enhance their therapeutic potential through rational design and combination therapies.