Unveiling the epigenetic landscape of AMPK regulation in cancer metabolism.

Cancer cells reprogram their metabolism not only through genetic mutations but also via reversible epigenetic modifications that alter gene expression without changing the DNA sequence. AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis. It plays a crucial role in cancer by modulating key metabolic pathways, including autophagy, lipid biosynthesis, and glucose utilization. Emerging evidence suggests that AMPK is tightly regulated by epigenetic mechanisms, including DNA methylation, histone remodeling, and non-coding RNAs, which influence AMPK gene expression, activation, and post-translational stability. Non-coding RNAs, including long non-coding RNAs, microRNAs, and circular RNAs, often engage in dynamic feedback loops with AMPK, coupling metabolic stress to transcriptional and epigenetic remodeling. In parallel, DNA methylation and histone modifications influence AMPK signaling indirectly through modulation of upstream regulators and directly via chromatin-associated functions of AMPK. Despite extensive characterization of AMPK function in cancer metabolism, the epigenetic mechanism governing its regulation remain comparatively underexplored. Distinct epigenetic signatures associated with AMPK regulation are being explored as a potential therapeutic target. This review provides a comprehensive overview of epigenetic regulation of AMPK in cancer and highlights its potential in the context of metabolic reprogramming and precision oncology.