NFS1 (cysteine desulfurase) is a mitochondrial enzyme that catalyzes L-cysteine desulfuration to form a cysteine persulfide intermediate, which serves as a sulfur donor for iron-sulfur (Fe-S) cluster biogenesis 12. As the rate-limiting enzyme in Fe-S cluster assembly, NFS1 is essential for maintaining iron-sulfur co-factors in multiple cellular proteins 3. NFS1 activity is particularly critical under high oxygen tension and protects cells from ferroptosis by maintaining adequate Fe-S cluster levels 3. Disease relevance spans multiple malignancies: NFS1 is upregulated in colorectal cancer, lung adenocarcinoma, hepatocellular carcinoma, and diffuse large B-cell lymphoma, where it confers chemotherapy resistance and ferroptosis protection 4356. Conversely, NFS1 deficiency is implicated in dilated cardiomyopathy and diabetic cardiomyopathy through impaired Fe-S cluster synthesis and mitochondrial dysfunction 78. Additionally, NFS1 was identified as a hub mitochondrial gene associated with osteoarthritis pathogenesis 9. Clinically, NFS1 inhibition represents a promising therapeutic strategy for enhancing platinum-based chemotherapy efficacy, particularly when combined with ferroptosis induction 4510.