# Phagocyte NADPH Oxidase NOX2-Derived Reactive Oxygen Species in Antimicrobial Defense: Mechanisms, Regulation, and Therapeutic Potential—A Narrative Review

## TL;DR

This review discusses how NOX2-derived reactive oxygen species (ROS) are crucial for fighting infections and managing inflammation, and explores new therapeutic strategies to control ROS for better treatment outcomes.

## Contribution

The paper provides a comprehensive overview of NOX2's role in antimicrobial defense and highlights novel therapeutic strategies targeting ROS regulation.

## Key findings

- NOX2-derived ROS are essential for pathogen killing and modulating inflammation through interactions with NF-κB, MAPK, and Nrf2 pathways.
- Both ROS deficiency and excess contribute to disease pathology, highlighting the need for balanced redox control.
- Emerging therapies include NOX2 inhibitors, redox-modulating peptides, and Nrf2 activators to manage oxidative stress.

## Abstract

ROS derived from NADPH oxidase, particularly NOX2, are central to antimicrobial defense, coupling direct pathogen killing with redox signaling that shapes inflammation. This narrative review integrates recent advances on NOX2 structure, assembly, and spatiotemporal control in phagocytes, and outlines how ROS interact with NF-κB, MAPK, and Nrf2 networks to coordinate microbicidal activity and immune modulation. We summarize evidence that both ROS deficiency, as in chronic granulomatous disease, and uncontrolled excess, as in sepsis and severe COVID-19, drive clinically significant pathology, emphasizing the need for precise redox balance. Emerging therapeutic strategies include selective NOX2 inhibitors that limit pathological oxidative bursts, redox-modulating peptides that disrupt upstream activation cues, and Nrf2 activators that enhance endogenous antioxidant capacity, with attention to dosing challenges that preserve host defense while mitigating tissue injury. Key gaps remain in biomarker standardization, real-time in vivo ROS monitoring, and translation from animal models to patients, motivating personalized, combination approaches to redox medicine in infectious diseases.