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Role of NADPH Oxidase following Traumatic Brain InjuryTraumatic brain injury (TBI) is a major cause of death and disability worldwide. Despite intense investigation, no neuroprotective agents for TBI have yet translated to the clinic. Recent efforts have focused on identifying potential therapeutic targets that underlie the secondary TBI pathology that evolves minutes to years following the initial injury. Oxidative stress is a key player in this complex cascade of secondary injury mechanisms and prominently contributes to neurodegeneration and neuroinflammation. In addition, the NLRP3 inflammasome, which produces pro-inflammatory signals, can become activated in response to oxidative stress and may exacerbate secondary pathology. NADPH oxidase (NOX) is a unique family of enzymes whose primary function is to produce reactive oxygen species (ROS). Human post-mortem and animal studies have identified elevated NOX2 and NOX4 levels in the injured brain, suggesting that NOX is involved in the pathogenesis of TBI. Our experiments demonstrate that targeting NOX, specifically NOX2 and NOX4, can reduce oxidative stress, attenuate neuroinflammation, reduce lesion size, and promote neuronal survival following TBI. In particular, deletion of NOX2 or inhibition of NOX can attenuate the increased expression and activation of the NLRP3 inflammasome via TXNIP- mediated pathway and decrease the production of pro-inflammatory factors, such as caspase-1 and IL-1β. We also demonstrate the novel findings that deletion of NOX4 can reduce neuronal oxidative damage evidenced by decreased DNA oxidation, lipid peroxidation, and protein nitration in the injured cerebral cortex. Mice lacking NOX4 also showed reduced cell death and neurodegeneration following TBI. Collectively, our results support the notion that targeting NOX enzymes can suppress neuroinflammatory secondary TBI pathology in addition to alleviating oxidative damage following injury. In addition, our inhibitor studies extend the critical window of efficacious TBI treatment, which further supports the pursuit of NOX as therapeutic targets.