"NADPH Oxidases: Central Regulators of Redox Signalling and Cellular Homeostasis".

INTRODUCTION: The seven isoforms of the NADPH oxidase (NOX) family-NOX1-5, DUOX1, and DUOX2-are multidomain enzymes that require distinct regulatory subunits for activation. These enzymes are major sources of reactive oxygen species (ROS), particularly the superoxide anion (O2·-), which exerts both cytotoxic and signalling effects. NADPH acts as a critical electron donor, maintaining cellular redox homeostasis and supporting anabolic metabolism. Dysregulated NOX activity has been linked to metabolic reprogramming in cancer and oxidative stress-induced complications in diabetes mellitus. METHODS: A focused systematic literature analysis was conducted using PubMed, Scopus, Web of Science, and Google Scholar databases (up to March 2025). Studies exploring NOX isoform regulation, ROS generation, NADPH-driven redox metabolism, and NOX-related signalling in cancer and diabetes were critically reviewed. RESULTS: Aberrant activation of the NOX1, NOX2, and NOX4 isoforms is strongly associated with oncogenic PI3K/Akt and MAPK signalling cascades, promoting metabolic reprogramming and antioxidant dependency in tumour cells. In diabetes, chronic hyperglycemia induces persistent NOX activation, leading to excessive ROS production and contributing to microvascular complications such as retinopathy, nephropathy, and neuropathy. DISCUSSION: NOX enzymes act as redox integrators that couple metabolic state to cellular signalling. Their dysregulation drives divergent yet overlapping pathogenic outcomes in cancer and diabetes. Selective NOX inhibition may normalize redox tone, restore metabolic flexibility, and enhance therapeutic responses. Understanding NOX isoform-specific regulation offers opportunities for biomarker development and combination therapy design. CONCLUSION: NOX1, NOX2, and NOX4 are key regulators of oxidative metabolism in cancer and diabetes. Targeting these isoforms represents a promising translational approach to modulate redox imbalance, suppress tumour progression, and mitigate diabetic microvascular complications.