Abstract
Nox4, originally termed Renox, was discovered in 2000. Since that time, our understanding of its structure and function has expanded enormously. Nox4 is ubiquitously expressed and is regulated at multiple levels, including epigenetic modification, transcriptional regulation, post-translational modification and interaction with partner proteins. It is unique among Nox enzymes in its lack of required cytosolic regulatory subunits and a propensity to produce hydrogen peroxide (H2O2) rather than superoxide. Nox4 has multiple subcellular localizations depending on cell type and environmental context. It regulates a number of fundamental cellular processes, including cytoskeletal structure and dynamics, proliferation, differentiation, survival, apoptosis, senescence, oxygen sensing, and metabolic homeostasis. Nox4 is required for normal organ functioning and certain physiological signaling processes, but it also contributes to multiple disease processes, especially fibrosis and diabetic vascular disease. It has been linked to cancer, myocardial hypertrophy, pulmonary disease, kidney disease and neurological conditions. Much remains to be learned about Nox4 in human disease and controversies remain about its contribution to physiology and pathophysiology. Attention has shifted to the development of specific Nox4 inhibitors, which will not only serve as a much-needed experimental tool, but also will help to realize the potential clinical utility of therapies targeting Nox4.
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Acknowledgments
LH received support from the Department of Veterans Affairs (BX006003), the Office of the Assistance Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program under award no. W81XWH-17-1-0443, and National Institutes of Health grants 1R21AG054766-01 and 1R41HL151043-01A1. KKG is supported by NIH grants R21AI163427 and R56HL152167.
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Hecker, L., Kato, K., Griendling, K.K. (2023). Nox4: From Discovery to Pathophysiology. In: Pick, E. (eds) NADPH Oxidases Revisited: From Function to Structure. Springer, Cham. https://doi.org/10.1007/978-3-031-23752-2_12
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