FDX1, also known as adrenodoxin, is a small mitochondrial protein and an iron-sulfur (Fe-S) cluster protein. It serves as an essential electron donor in multiple cellular processes. FDX1 is involved in pathways such as steroidogenesis, heme a and lipoyl cofactor biosyntheses, and is crucial for the biogenesis of mitochondrial cytochrome c oxidase [4,6]. It also plays a significant role in the regulation of cuproptosis, a form of programmed cell death related to high copper concentrations [1,3,5,7]. Genetic models, like knockout (KO) models, can be used to study its functions in vivo.

In hepatocellular carcinoma (HCC), FDX1 down-regulation promotes cell proliferation, invasion, and metastasis. It activates mitophagy and the PI3K/AKT signaling pathway by increasing ROS production [2]. In clear cell renal cell carcinoma (ccRCC), FDX1 acts as a tumor suppressor, and the miR-21-5p/FDX1 axis impacts the tumor microenvironment and immune cell infiltration [5]. In endometriosis, FDX1 promotes cuproptosis in cells via the G6PD-mediated redox homeostasis pathway, suppressing cell proliferation and metastasis [3]. In thyroid cancer, FDX1 promotes cuprotosis by regulating the lipoylation of DLAT, thus inhibiting the cancer's malignant progression [7].

In summary, FDX1 is essential for multiple mitochondrial-related metabolic processes and plays a significant role in the regulation of cuproptosis. Through KO or other loss-of-function models, its role in various cancers, such as HCC, ccRCC, endometriosis-associated tumors, and thyroid cancer, has been revealed. Understanding FDX1 functions can potentially provide new therapeutic strategies for these diseases.

References:

1. Sun, Lianhui, Zhang, Yuan, Yang, Boyu, Fan, Guangjian, Huang, Chen. 2023. Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer. In Nature communications, 14, 6523. doi:10.1038/s41467-023-42025-8. https://pubmed.ncbi.nlm.nih.gov/37863889/

2. Sun, Bo, Ding, Peng, Song, Yinghui, Peng, Chuang, Liu, Sulai. 2024. FDX1 downregulation activates mitophagy and the PI3K/AKT signaling pathway to promote hepatocellular carcinoma progression by inducing ROS production. In Redox biology, 75, 103302. doi:10.1016/j.redox.2024.103302. https://pubmed.ncbi.nlm.nih.gov/39128228/

3. Lu, Jiayi, Ling, Xi, Sun, Yonghong, Han, Xue, Yu, Zhenhai. 2023. FDX1 enhances endometriosis cell cuproptosis via G6PD-mediated redox homeostasis. In Apoptosis : an international journal on programmed cell death, 28, 1128-1140. doi:10.1007/s10495-023-01845-1. https://pubmed.ncbi.nlm.nih.gov/37119432/

4. Schulz, Vinzent, Basu, Somsuvro, Freibert, Sven-A, Stehling, Oliver, Lill, Roland. 2022. Functional spectrum and specificity of mitochondrial ferredoxins FDX1 and FDX2. In Nature chemical biology, 19, 206-217. doi:10.1038/s41589-022-01159-4. https://pubmed.ncbi.nlm.nih.gov/36280795/

5. Xie, Mingyue, Cheng, Bo, Yu, Shuang, Dai, Rongyang, Wang, Ronghao. 2022. Cuproptosis-Related MiR-21-5p/FDX1 Axis in Clear Cell Renal Cell Carcinoma and Its Potential Impact on Tumor Microenvironment. In Cells, 12, . doi:10.3390/cells12010173. https://pubmed.ncbi.nlm.nih.gov/36611966/

6. Zulkifli, Mohammad, Okonkwo, Adriana U, Gohil, Vishal M. 2023. FDX1 Is Required for the Biogenesis of Mitochondrial Cytochrome c Oxidase in Mammalian Cells. In Journal of molecular biology, 435, 168317. doi:10.1016/j.jmb.2023.168317. https://pubmed.ncbi.nlm.nih.gov/37858707/

7. Chen, Gaoxiang, Zhang, Jianan, Teng, Weifeng, Luo, Yong, Ji, Xiaochun. 2023. FDX1 inhibits thyroid cancer malignant progression by inducing cuprotosis. In Heliyon, 9, e18655. doi:10.1016/j.heliyon.2023.e18655. https://pubmed.ncbi.nlm.nih.gov/37554785/