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This review integrates recent advances in structural biology, immunometabolism, toxicology, and systems biology to provide an updated, comprehensive, and accessible view of NOX biology. Recent\u00a0advances in\u00a0high\u2011resolution cryo-EM, AlphaFold\u2011based modeling and molecular dynamics studies\u00a0have provided new insights into\u00a0NOX architecture, catalytic sites, post\u2011translational modifications and\u00a0regulatory mechanisms, and docking interfaces for RAC1 and p47\n                    <jats:sup>\n                      <jats:italic>phox<\/jats:italic>\n                    <\/jats:sup>\n                    .\u00a0Emerging evidence further indicates that cellular\u00a0NOX-derived ROS can\u00a0reprogram macrophage and T-cell metabolism, stabilize HIF-1\u03b1, and tune the balance between effector and regulatory states, thereby linking NOX activity to checkpoint control and tumor immune escape. A second focus is on how real\u2011world pollutants converge on NOX isoforms as proximal\u00a0mediators of redox signaling across lung, vascular, hepatic, renal, and neural tissues. NOX activation during cellular injury may\u00a0contribute to oxidative stress, mitochondrial dysfunction, inflammasome activation, and fibrotic signaling,\u00a0through extracellular vesicles, lipid rafts, and noncoding RNAs. Finally, the review evaluates emerging\u00a0therapeutic strategies, including\u00a0isoform-selective\/pan-NOX\/peptide inhibitors, and nanozymes. It also discusses emerging approaches such as\u00a0exosome-based biomarkers, network pharmacology, and machine learning for patient stratification and pharmacodynamic monitoring. By highlighting key mechanistic gaps and translational opportunities, this review establishes NOXs as actionable nodal regulators at the intersection of immunity, metabolism, environmental exposure, and human disease.\n                  <\/jats:p>","DOI":"10.1038\/s41423-026-01447-2","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T05:03:10Z","timestamp":1787547790000},"page":"1055-1109","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NADPH oxidases in immunometabolism and disease pathology: mechanistic networks, pollutant triggers, and therapeutic frontiers"],"prefix":"10.1038","volume":"23","author":[{"given":"M.","family":"Thakur","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Mutyala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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