Redox-Guided Metabolic Control in Cancer: Integration of the Reactive Oxygen Species-AMP-Activated Protein Kinase-Sirtuin Axis in Tumour Adaptation and Therapy.

Abstract

Cancer progression is tightly linked to metabolic reprogramming and persistent redox imbalance, which together sustain tumour growth while simultaneously creating exploitable vulnerabilities. Reactive oxygen species (ROS), once viewed solely as damaging metabolic by-products, are now recognized as dynamic signalling molecules that regulate energy homeostasis, mitochondrial function, and cell-fate decisions. Central to this regulation is the ROS-AMP-activated protein kinase (AMPK)-sirtuin axis, an evolutionarily conserved network that integrates redox signals with cellular energy sensing and NAD⁺ metabolism. AMPK responds to energetic and oxidative stress by suppressing anabolic pathways and promoting catabolic adaptation, whereas NAD⁺-dependent sirtuins-particularly SIRT1, SIRT3, and SIRT6-translate metabolic and redox cues into coordinated transcriptional, epigenetic, and mitochondrial responses. At moderate ROS levels, activation of this axis restores metabolic equilibrium, enhances antioxidant defences, and preserves genomic stability; in contrast, excessive or sustained oxidative stress overwhelms adaptive capacity, driving mitochondrial dysfunction and apoptosis in metabolically compromised tumour cells. This review provides a mechanistic and translational synthesis of how ROS regulate AMPK and sirtuin activity through both energy-dependent and redox-dependent mechanisms, thereby reshaping cancer metabolism and redox homeostasis. We examine the context-dependent roles of individual sirtuin isoforms across nuclear, cytosolic, and mitochondrial compartments and discuss emerging therapeutic strategies targeting this network, including pharmacological AMPK activators, NAD⁺ boosters, sirtuin modulators, and redox-active nutraceuticals. Finally, we highlight key translational challenges and future directions, emphasizing biomarker-guided precision, isoform-specific targeting, and controlled modulation of ROS signalling. Collectively, this framework positions the ROS-AMPK-Sirtuin axis as a foundation for redox-guided metabolic oncology.