Nfs1, a cysteine desulfurase, is a rate-limiting enzyme in iron-sulfur (Fe-S) cluster biogenesis. Fe-S clusters are vital components of numerous essential proteins, especially in mitochondrial respiratory chain complexes I-III. The biogenesis of Fe-S clusters is a multi-step process where Nfs1, in complex with ISD11 and ACP, initiates the first step [5].

Loss-of-function studies have revealed significant roles of Nfs1. In colorectal cancer, loss of NFS1 enhanced the sensitivity of CRC cells to oxaliplatin, and NFS1 deficiency synergized with oxaliplatin to trigger PANoptosis [1]. In lung tumours, suppression of NFS1 affected tumour growth, as metastatic or primary lung tumours could not grow despite NFS1 suppression, and NFS1 protected cells from ferroptosis [2]. In gastric cancer, knockdown of NFS1 reduced cell viability, migration, invasion and promoted ferroptosis, with NFS1 inhibiting ferroptosis by regulating the STAT3 pathway [3]. Also, in sevoflurane-induced neurotoxicity in neonatal mice, overexpression of Nfs1 relieved neurotoxicity and cognitive dysfunction by suppressing oxidative stress and ferroptosis [4].

In conclusion, Nfs1 is crucial for Fe-S cluster biogenesis and has far-reaching impacts on various biological processes and disease conditions. Model-based research, especially loss-of-function experiments, has demonstrated its role in cancer chemosensitivity, tumour growth, ferroptosis regulation, and neurotoxicity, providing potential therapeutic targets for related diseases.

References:

1. Lin, Jin-Fei, Hu, Pei-Shan, Wang, Yi-Yu, Xu, Rui-Hua, Qiu, Miao-Zhen. 2022. Phosphorylated NFS1 weakens oxaliplatin-based chemosensitivity of colorectal cancer by preventing PANoptosis. In Signal transduction and targeted therapy, 7, 54. doi:10.1038/s41392-022-00889-0. https://pubmed.ncbi.nlm.nih.gov/35221331/

2. Alvarez, Samantha W, Sviderskiy, Vladislav O, Terzi, Erdem M, Birsoy, Kıvanç, Possemato, Richard. 2017. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. In Nature, 551, 639-643. doi:10.1038/nature24637. https://pubmed.ncbi.nlm.nih.gov/29168506/

3. Jiang, You, Li, Liqiang, Li, Wenbo, Wu, Yuee, Wang, Zhengguang. 2024. NFS1 inhibits ferroptosis in gastric cancer by regulating the STAT3 pathway. In Journal of bioenergetics and biomembranes, 56, 573-587. doi:10.1007/s10863-024-10038-7. https://pubmed.ncbi.nlm.nih.gov/39254861/

4. Zhang, Yang, Liu, Xinru, Xie, Lijuan, Li, Xiaohong, Zhang, Congli. . Overexpression of Nfs1 Cysteine Desulphurase Relieves Sevoflurane-Induced Neurotoxicity and Cognitive Dysfunction in Neonatal Mice Via Suppressing Oxidative Stress and Ferroptosis. In Journal of biochemical and molecular toxicology, 38, e70051. doi:10.1002/jbt.70051. https://pubmed.ncbi.nlm.nih.gov/39488760/

5. Hershkovitz, Tova, Kurolap, Alina, Tal, Galit, Mandel, Hanna, Baris Feldman, Hagit. 2020. A recurring NFS1 pathogenic variant causes a mitochondrial disorder with variable intra-familial patient outcomes. In Molecular genetics and metabolism reports, 26, 100699. doi:10.1016/j.ymgmr.2020.100699. https://pubmed.ncbi.nlm.nih.gov/33457206/