Sfxn4, a member of the sideroflexin family, is a nuclear-encoded mitochondrial protein. It localizes to the mitochondrial inner membrane and is essential for normal mitochondrial function, playing a crucial role in iron-sulfur (Fe-S) cluster biogenesis, iron homeostasis, mitochondrial respiration, and heme synthesis [5]. It has also been implicated in metabolic pathways such as oxidative phosphorylation [1]. Genetic models, especially knockout models, have been pivotal in elucidating its functions.

Knockdown of Sfxn4 in vitro and in vivo has revealed multiple important roles. In ovarian cancer cells, Sfxn4 knockdown inhibits Fe-S biogenesis, leading to excess iron accumulation, oxidative stress, and inhibition of DNA repair pathways as DNA repair enzymes rely on Fe-S clusters. This dual mechanism increases ovarian cancer cell sensitivity to DNA-damaging drugs and DNA repair inhibitors, even in drug-resistant cells, and profoundly inhibits tumor growth in a mouse model of ovarian cancer metastasis [3]. In hepatocellular carcinoma (HCC), knockdown of Sfxn4 inhibits cell proliferation, migration, and invasion, both in vitro and in vivo, and is associated with decreased expression of cyclin D1 and MMP2 [1]. In osteosarcoma cells, knockdown studies suggest that Sfxn4 promotes cell growth, migration, and invasion [2]. In zebrafish, sfxn4 knockdown recapitulates mitochondrial respiratory defects and macrocytic anemia seen in human cases with SFXN4 mutations [4].

In summary, Sfxn4 is essential for mitochondrial-related functions including Fe-S cluster formation, iron metabolism, and respiration. Knockout and knockdown models across various cancer types and disease conditions, such as ovarian cancer, HCC, osteosarcoma, and mitochondriopathy with macrocytic anemia, have highlighted its role in promoting cancer cell progression and in disease pathogenesis. Understanding Sfxn4 functions through these models may offer potential therapeutic targets for related diseases.

References:

1. Du, Zhipeng, Zhang, Zhongchao, Han, Xu, Liu, Mei, Rao, Caijun. 2023. Comprehensive Analysis of Sideroflexin 4 in Hepatocellular Carcinoma by Bioinformatics and Experiments. In International journal of medical sciences, 20, 1300-1315. doi:10.7150/ijms.86990. https://pubmed.ncbi.nlm.nih.gov/37786439/

2. Wang, Yizhuo, Wang, Xin, Liu, Yang, Zheng, Yufu, Qi, Quan. 2024. A novel hypoxia- and lactate metabolism-related prognostic signature to characterize the immune landscape and predict immunotherapy response in osteosarcoma. In Frontiers in immunology, 15, 1467052. doi:10.3389/fimmu.2024.1467052. https://pubmed.ncbi.nlm.nih.gov/39569192/

3. Tesfay, Lia, Paul, Bibbin T, Hegde, Poornima, Torti, Suzy V, Torti, Frank M. 2022. Complementary anti-cancer pathways triggered by inhibition of sideroflexin 4 in ovarian cancer. In Scientific reports, 12, 19936. doi:10.1038/s41598-022-24391-3. https://pubmed.ncbi.nlm.nih.gov/36402786/

4. Hildick-Smith, Gordon J, Cooney, Jeffrey D, Garone, Caterina, DiMauro, Salvatore, Paw, Barry H. 2013. Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4. In American journal of human genetics, 93, 906-14. doi:10.1016/j.ajhg.2013.09.011. https://pubmed.ncbi.nlm.nih.gov/24119684/

5. Paul, Bibbin T, Tesfay, Lia, Winkler, C R, Torti, Frank M, Torti, Suzy V. 2019. Sideroflexin 4 affects Fe-S cluster biogenesis, iron metabolism, mitochondrial respiration and heme biosynthetic enzymes. In Scientific reports, 9, 19634. doi:10.1038/s41598-019-55907-z. https://pubmed.ncbi.nlm.nih.gov/31873120/