CYBB, also known as NOX2 or gp91phox, encodes a component of the phagocytic Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This enzyme is crucial for generating superoxide, which acts as a precursor for hydrogen peroxide and other reactive oxygen species (ROS) in neutrophils, playing key roles in killing bacteria, regulating the inflammatory response, and being involved in processes like macrophage polarization and ferroptosis [3,4,5,6].

In sepsis, machine-learning analysis identified CYBB as an independent predictor of poor survival, and the administration of sulforaphane (SFN) alleviated murine lung neutrophil extracellular trap (NET) expression and injury, accompanied by a change in whole-blood CYBB mRNA level, suggesting its potential as a sepsis treatment target [1]. In Mycobacterium leprae-infected monocyte-derived macrophages, CYBB-mediated ferroptosis was found to be associated with immunosuppression, promoting the M2 polarization of macrophages and facilitating the immune escape of the bacteria [2]. In mesenchymal glioblastoma, CYBB conferred chemotherapy and ferroptosis resistance via the Nrf2/SOD2 axis [4]. Mutations in CYBB cause X-linked chronic granulomatous disease (CGD), leading to susceptibility to recurrent fungal and bacterial infections [5].

In conclusion, CYBB is essential for the function of the NADPH oxidase complex and the generation of ROS, which impacts multiple biological processes. The study of CYBB, especially through genetic models, has provided insights into its role in diseases such as sepsis, leprosy, glioblastoma, and CGD, highlighting its potential as a therapeutic target.