ISCU is a cytoplasmic scaffold protein essential for iron-sulfur cluster assembly, serving as the structural platform for [2Fe-2S] and [4Fe-4S] cluster biosynthesis within the cytoplasmic Fe-S assembly complex 1. The protein functions as a molecular adapter that coordinates with cysteine desulfurase NFS1 and other components to facilitate Fe-S cluster transfer to target proteins 2. Zinc binding to ISCU modulates desulfurase activity and regulates the assembly process 3. Beyond classical Fe-S assembly, ISCU exhibits unexpected immunological functions: it promotes M2 macrophage polarization by sequestering p53 in the cytoplasm, reducing nuclear p53 and relieving transcriptional repression of xCT and Arg1, thereby enhancing macrophage immunosuppression 4. MicroRNA-210 suppresses ISCU expression to reprogram macrophage metabolism, shifting from oxidative phosphorylation to glycolysis during inflammatory responses 5, and targeting ISCU-miR-210 axis induces ferroptosis in hepatic stellate cells, ameliorating metabolic dysfunction-associated steatohepatitis fibrosis 6. Clinical relevance includes association with myopathy with exercise intolerance and potential implications for immunotherapy resistance in esophageal squamous cell carcinoma.