NCF2, also known as Neutrophil Cytosolic Factor 2, encodes the p67phox protein which is a key component of the NADPH oxidase complex. This complex is essential for generating reactive oxygen species (ROS), playing a crucial role in the immune system's defense against pathogens. It is involved in immune-related biological processes, and its dysregulation can impact various physiological and pathological conditions [2,3,7].

Mutations in NCF2 can lead to chronic granulomatous disease (CGD), an autosomal recessive primary immunodeficiency disorder. A novel c.855G>C NCF2 mutation was found in three patients, presenting with diverse clinical phenotypes such as interstitial lung disease, severe pneumonia, lymphadenitis, recurrent skin abscesses, and discoid lupus erythematosus [1]. Another novel homozygous variant (c.290C > A) in NCF2 was identified in a patient with early-onset severe disease, including destructive osteomyelitis, necrotizing lymphadenopathy, and disseminated BCG infection [6]. In hepatocellular carcinoma (HCC), high NCF2 expression predicts an adverse prognosis and more M2 macrophages infiltration [2]. In atherosclerosis, NCF2 is a diagnostic gene and may be involved in the formation of the necrotic core by regulating macrophage ferroptosis [3]. In bladder cancer, lncRNA BLACAT3 enhances NCF2 transcription to promote angiogenesis and hematogenous metastasis [4]. In chemotherapy-induced alopecia, S100A8 promotes ferroptosis via the NCF2/NOX2 pathway [5]. In pan-cancer analysis, NCF2 is dysregulated in many cancer types, impacts the tumor microenvironment, and is an independent prognostic factor for leukemia. In vitro, NCF2 knockdown affects cell proliferation, apoptosis, and cell cycle dynamics in AML cell lines [7].

In conclusion, NCF2 is crucial for the proper functioning of the NADPH oxidase complex and immune-related processes. Research on NCF2, especially through studies of its mutations in disease models, has revealed its significant roles in multiple diseases including immunodeficiency disorders, various cancers, atherosclerosis, and chemotherapy-induced alopecia. These findings contribute to a better understanding of disease mechanisms and may offer potential targets for therapeutic intervention.

References:

1. Roth, Idit Lachover, Salamon, Pazit, Freund, Tal, Bentur, Lea, Hagin, David. 2020. Novel NCF2 Mutation Causing Chronic Granulomatous Disease. In Journal of clinical immunology, 40, 977-986. doi:10.1007/s10875-020-00820-8. https://pubmed.ncbi.nlm.nih.gov/32666379/

2. Huang, Ning, Zhang, Jing, Kuang, Shuwen, Liu, Mei, Wang, Liming. 2023. Role of NCF2 as a potential prognostic factor and immune infiltration indicator in hepatocellular carcinoma. In Cancer medicine, 12, 8991-9004. doi:10.1002/cam4.5597. https://pubmed.ncbi.nlm.nih.gov/36680322/

3. Li, Minhui, Xin, Siyuan, Gu, Ruiyuan, Zhang, Ruijing, Dong, Honglin. 2022. Novel Diagnostic Biomarkers Related to Oxidative Stress and Macrophage Ferroptosis in Atherosclerosis. In Oxidative medicine and cellular longevity, 2022, 8917947. doi:10.1155/2022/8917947. https://pubmed.ncbi.nlm.nih.gov/36035208/

4. Xie, Jinbo, Zhang, Hui, Wang, Keyi, Mao, Weipu, Peng, Bo. 2023. M6A-mediated-upregulation of lncRNA BLACAT3 promotes bladder cancer angiogenesis and hematogenous metastasis through YBX3 nuclear shuttling and enhancing NCF2 transcription. In Oncogene, 42, 2956-2970. doi:10.1038/s41388-023-02814-3. https://pubmed.ncbi.nlm.nih.gov/37612524/

5. Xu, Wen, Li, Yujie, Wan, Sheng, Guan, Cuiping, Song, Xiuzu. 2025. S100A8 induces cyclophosphamide-induced alopecia via NCF2/NOX2-mediated ferroptosis. In Free radical biology & medicine, 230, 112-126. doi:10.1016/j.freeradbiomed.2025.02.014. https://pubmed.ncbi.nlm.nih.gov/39947495/

6. AlKhater, Suzan A, Deswarte, Caroline, Casanova, Jean-Laurent, Bustamante, Jacinta. 2020. A novel variant in the neutrophil cytosolic factor 2 (NCF2) gene results in severe disseminated BCG infectious disease: A clinical report and literature review. In Molecular genetics & genomic medicine, 8, e1237. doi:10.1002/mgg3.1237. https://pubmed.ncbi.nlm.nih.gov/32281309/

7. Zhong, Fangfang, Zeng, Yan, Yan, Yuzhi, Liu, Wenjun, Liu, Chunyan. 2024. Comprehensive multi-omics analysis of the prognostic value and immune signature of NCF2 in pan-cancer and its relationship with acute myeloid leukemia. In International immunopharmacology, 143, 113364. doi:10.1016/j.intimp.2024.113364. https://pubmed.ncbi.nlm.nih.gov/39393272/