CIAO1 is a core component of the cytosolic iron-sulfur assembly (CIA) complex that mediates incorporation of [4Fe-4S] clusters into extramitochondrial Fe/S proteins 1. As part of the CIA targeting complex, CIAO1 interacts with CIAO2A/CIAO2B and MMS19 to facilitate maturation of diverse cytosolic-nuclear Fe/S proteins involved in DNA metabolism 2. The CIAO1:CIAO2B:MMS19 complex specifically matures most cytosolic-nuclear Fe/S proteins, while CIAO1:CIAO2A matures aconitase and stabilizes IREB2 3. CIAO1 integrates de novo Fe/S cluster biogenesis with downstream delivery to recipient proteins 4. Biallelic CIAO1 loss-of-function mutations cause neuromuscular disorder characterized by proximal muscle weakness, respiratory insufficiency, CNS symptoms including learning difficulties, iron deposition in brain nuclei, and anemia 15. Pathogenic variants show reduced protein stability and fail to recruit Fe/S recipient proteins, compromising DNA helicase, polymerase, and repair enzyme activities 1. A heterozygous missense variant (Val67Ile) co-segregates with familial Alzheimer's disease and promotes CIAO1 interaction with amyloid-β protein precursor 6. CIAO1 deficiency also causes pleiotropic effects on proteome, metabolome, and lipidome profiles, with particular impact on antiviral immunity 5. These findings establish CIAO1 as essential for cytoplasmic Fe/S protein maturation and human health.