AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis

The orchestration of cellular metabolism requires the integration of signals related to energy stores and nutrient availability through multiple overlapping mechanisms. AMP-activated protein kinase (AMPK) is a pivotal energy sensor that responds to reductions in adenylate charge; however, studies over the past decade have also positioned AMPK as a key integrator of nutrient-derived signals that coordinate metabolic function. This Review highlights recent advances in our understanding of how AMPK senses nutrients and regulates metabolic activity across tissues, timescales and cell types. These effects are mediated through the phosphorylation of substrates involved in metabolite trafficking, mitochondrial function, autophagy, transcription, ubiquitination, proliferation and cell survival pathways, including ferroptosis. Particular attention is given to the role of AMPK in the pathophysiology of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, cardiovascular and renal diseases, neurodegenerative disorders and cancer. Collectively, these findings reinforce AMPK as a central metabolic node that aligns cellular behaviour with energetic demand. Continued investigation into its nutrient-sensing mechanisms holds promise for identifying new strategies to restore metabolic balance in disease.