Nfs1, also known as cysteine desulfurase, is a rate-limiting enzyme in iron-sulfur (Fe-S) cluster biogenesis. Fe-S clusters are cofactors involved in diverse essential biological processes. Nfs1 is crucial for generating activated sulfur, which is essential for the initial step of Fe-S cluster assembly in mitochondria. It is associated with pathways related to cellular iron homeostasis and redox regulation, and is of great biological importance in maintaining normal cell function [4].

Loss-of-function studies have revealed significant roles of Nfs1. In colorectal cancer, loss of NFS1 enhanced the sensitivity of CRC cells to oxaliplatin, as NFS1 deficiency synergized with oxaliplatin to trigger PANoptosis by increasing intracellular reactive oxygen species (ROS) levels. Also, phosphorylation of NFS1 by oxaliplatin-based oxidative stress prevented PANoptosis in a phosphorylation-dependent manner [1]. In lung tumours, NFS1 was found to be under positive selection. Suppression of NFS1 in metastatic or primary lung tumours inhibited their growth, as NFS1 protects cells from ferroptosis, especially important for maintaining iron-sulfur co-factors in a high-oxygen environment [2]. In gastric cancer, knockdown of NFS1 reduced cell viability, migration, and invasion, and promoted ferroptosis by inhibiting the STAT3 pathway [3].

In conclusion, Nfs1 plays essential roles in maintaining cellular iron-sulfur cluster biogenesis, redox homeostasis, and cell survival. Loss-of-function models, such as those in colorectal, lung, and gastric cancer, have shown its significance in chemosensitivity and tumour cell survival, suggesting it could be a potential therapeutic target in these cancer types.