AMPK-Mediated Lipid Metabolic Reprogramming in Cancer: From Mechanisms to Targeted Therapies.

Abstract

AMP-activated protein kinase (AMPK), a key regulator of cellular energy metabolism, is activated under conditions of energy stress to restore metabolic homeostasis by promoting catabolic pathways and inhibiting anabolic processes such as lipid synthesis. Multiple key molecules involved in lipid metabolism are regulated by AMPK, and its role in cancer progression through lipid metabolism is dual-edged. On the one hand, AMPK suppresses lipogenesis by inhibiting key regulators such as SREBP, ACC, and HMGCR, thereby limiting the biosynthetic substrates and membrane lipid availability required for tumor cell proliferation. On the other hand, AMPK activation may also enhance fatty acid oxidation and metabolic adaptation, which can support growth and survival under nutrient limitation, hypoxia, or therapeutic stress. This dual role presents therapeutic challenges but also creates opportunities for context-specific intervention. In this review, we summarize the mechanisms by which AMPK regulates lipid metabolism in cancer and discuss the current progress, therapeutic potential, and limitations of AMPK-modulating strategies.