Nox4, short for NADPH oxidase 4, is a major source of reactive oxygen species (ROS). It is involved in various biological processes, such as regulating redox and metabolic homeostasis, and is associated with pathways like mitochondrial metabolism and immune-related signaling. Its function is crucial in maintaining normal cellular function, and genetic models, including gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its roles.

In Alzheimer's disease, the protein levels of Nox4 were elevated in impaired astrocytes, promoting ferroptosis via oxidative stress-induced lipid peroxidation and mitochondrial metabolism impairment [1]. In cancer-associated fibroblasts, inhibition of Nox4 "normalized" the cells to a quiescent phenotype, promoting intratumoral CD8+ T-cell infiltration and restoring immunotherapy response in CAF-rich tumors [2]. In HCC, Nox4 gene deletions were frequent, correlating with higher tumor grade. Loss of Nox4 induced metabolic reprogramming in a Nrf2/MYC-dependent manner to promote HCC progression [3]. In NSCLC, elevated Nox4 promoted tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling [4]. In obesity-related liver diseases, deletion of Nox4 in hepatocytes promoted the progression to non-alcoholic steatohepatitis and fibrosis, while overexpression tempered its development [5]. In NSCLC, tumoral Nox4 recruited M2 tumor-associated macrophages via ROS/PI3K-dependent cytokine production to promote tumor growth [6]. In benign prostate hyperplasia, inhibition of AR/TGF-β/NOX4 by apocynin suppressed inflammation and proliferation [7]. In Parkinson's disease, elevation of Nox4 in hippocampal astrocytes cooperated with MPO and OPN inflammatory cytokines through mitochondrial aberration [8]. In cardiac hypertrophy, delivery of Nox4 siRNA using engineered small extracellular vesicles improved cardiac function [9]. In HCC after incomplete radiofrequency ablation, upregulation of Nox4 promoted cell survival by inducing mitophagy via Nrf2/PINK1 [10].

In conclusion, Nox4 plays essential roles in multiple biological processes and disease conditions. KO/CKO mouse models and other loss-of-function experiments have revealed its significance in neurodegenerative diseases like Alzheimer's and Parkinson's, various cancers including HCC and NSCLC, obesity-related liver diseases, and cardiac hypertrophy. These studies help us understand the underlying mechanisms and provide potential therapeutic targets for these diseases.

References:

1. Park, Min Woo, Cha, Hyeon Woo, Kim, Junhyung, Yoo, Ik Dong, Moon, Jong-Seok. 2021. NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases. In Redox biology, 41, 101947. doi:10.1016/j.redox.2021.101947. https://pubmed.ncbi.nlm.nih.gov/33774476/

2. Ford, Kirsty, Hanley, Christopher J, Mellone, Massimiliano, Savelyeva, Natalia, Thomas, Gareth J. 2020. NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors. In Cancer research, 80, 1846-1860. doi:10.1158/0008-5472.CAN-19-3158. https://pubmed.ncbi.nlm.nih.gov/32122909/

3. Peñuelas-Haro, Irene, Espinosa-Sotelo, Rut, Crosas-Molist, Eva, Bertran, Esther, Fabregat, Isabel. 2022. The NADPH oxidase NOX4 regulates redox and metabolic homeostasis preventing HCC progression. In Hepatology (Baltimore, Md.), 78, 416-433. doi:10.1002/hep.32702. https://pubmed.ncbi.nlm.nih.gov/35920301/

4. Liu, Wen-Jing, Wang, Lin, Zhou, Feng-Mei, Qiu, Jian-Ge, Jiang, Bing-Hua. 2023. Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC. In Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 70, 100987. doi:10.1016/j.drup.2023.100987. https://pubmed.ncbi.nlm.nih.gov/37392558/

5. Greatorex, Spencer, Kaur, Supreet, Xirouchaki, Chrysovalantou E, Watt, Matthew J, Tiganis, Tony. 2023. Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity. In The Journal of clinical investigation, 134, . doi:10.1172/JCI162533. https://pubmed.ncbi.nlm.nih.gov/38060313/

6. Zhang, Jiahao, Li, Huachao, Wu, Qipeng, Zhang, Luyong, Liu, Bing. 2019. Tumoral NOX4 recruits M2 tumor-associated macrophages via ROS/PI3K signaling-dependent various cytokine production to promote NSCLC growth. In Redox biology, 22, 101116. doi:10.1016/j.redox.2019.101116. https://pubmed.ncbi.nlm.nih.gov/30769285/

7. Jin, Bo-Ram, Kim, Hyo-Jung, Na, Jung-Hyun, Lee, Won-Kyu, An, Hyo-Jin. 2023. Targeting benign prostate hyperplasia treatments: AR/TGF-β/NOX4 inhibition by apocynin suppresses inflammation and proliferation. In Journal of advanced research, 57, 135-147. doi:10.1016/j.jare.2023.04.006. https://pubmed.ncbi.nlm.nih.gov/37061215/

8. Boonpraman, Napissara, Yoon, Sunmi, Kim, Chae Young, Moon, Jong-Seok, Yi, Sun Shin. 2023. NOX4 as a critical effector mediating neuroinflammatory cytokines, myeloperoxidase and osteopontin, specifically in astrocytes in the hippocampus in Parkinson's disease. In Redox biology, 62, 102698. doi:10.1016/j.redox.2023.102698. https://pubmed.ncbi.nlm.nih.gov/37058998/

9. Kang, Ji-Young, Mun, Dasom, Chun, Yumin, Yun, Nuri, Joung, Boyoung. . Engineered small extracellular vesicle-mediated NOX4 siRNA delivery for targeted therapy of cardiac hypertrophy. In Journal of extracellular vesicles, 12, e12371. doi:10.1002/jev2.12371. https://pubmed.ncbi.nlm.nih.gov/37795828/

10. Peng, Chao, Li, Xi, Ao, Feng, Mao, Junjie, Zhou, Bin. 2023. Mitochondrial ROS driven by NOX4 upregulation promotes hepatocellular carcinoma cell survival after incomplete radiofrequency ablation by inducing of mitophagy via Nrf2/PINK1. In Journal of translational medicine, 21, 218. doi:10.1186/s12967-023-04067-w. https://pubmed.ncbi.nlm.nih.gov/36964576/