Nox4, also known as NADPH oxidase 4, is a major source of reactive oxygen species (ROS). It is involved in multiple biological processes, regulating redox and metabolic homeostasis, and is associated with pathways like mitochondrial metabolism, PI3K/Akt signaling, and Nrf2-related antioxidant defense [1,2,4,5]. Nox4 is of great biological importance as it plays roles in various physiological and pathological conditions. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying its functions.

In Alzheimer's disease, elevated Nox4 protein levels in astrocytes promote ferroptosis through oxidative stress-induced lipid peroxidation via mitochondrial metabolism impairment [1]. In cancer, Nox4 has diverse effects. In hepatocellular carcinoma (HCC), its deletion promotes tumor progression, as it negatively regulates MYC, which mediates mitochondrial dynamics and metabolic reprogramming [2]. In non-small-cell lung cancer (NSCLC), elevated Nox4 promotes tumorigenesis and EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling [3]. Nox4 also recruits M2 tumor-associated macrophages in NSCLC to promote tumor growth [5]. In obesity-related liver diseases, NOX4 deletion in hepatocytes of high-fat diet-fed obese mice promotes NASH and fibrosis, while overexpression tempers their development [4]. In Parkinson's disease, elevated Nox4 in hippocampal astrocytes cooperates with MPO and OPN inflammatory cytokines through mitochondrial aberration [6].

In conclusion, Nox4 is crucial in regulating redox and metabolic balance. KO/CKO mouse models have revealed its significance in diseases like neurodegenerative disorders, cancer, and obesity-related liver diseases. Understanding Nox4's functions provides insights into disease mechanisms and potential therapeutic targets.