Redox enzyme networks shaping cancer drug metabolism and therapeutic resistance

Multidrug resistance remains a major challenge in cancer therapy, arising from complex adaptive mechanisms that enable tumor cells to survive pharmacological stress. Among these mechanisms, redox-regulating enzymes play a pivotal role by maintaining intracellular redox balance and supporting cellular defense systems during chemotherapy. Beyond their classical detoxification functions, redox enzymes critically influence cancer drug metabolism by modulating bioactivation, detoxification efficiency, and NADPH-dependent redox homeostasis. Glutathione-dependent enzymes, NAD(P)H-linked oxidoreductases, and redox-sensitive signaling regulators collectively drive metabolic reprogramming and stress tolerance in drug-treated cancer cells. Rather than acting as isolated determinants of drug response, these enzymes function as interconnected and adaptive networks that dynamically respond to therapeutic pressure. Such network-level organization enables compensatory mechanisms that promote metabolic flexibility and reduced treatment response. This review highlights how redox enzyme networks shape cancer drug metabolism and treatment outcomes, emphasizing their implications for drug clearance, metabolic adaptation, and treatment efficacy. Understanding these systems from a network-based perspective may provide a conceptual foundation for metabolism-aware therapeutic strategies aimed at overcoming drug resistance.