Recent discoveries reveal that frataxin (FXN) and ferredoxin 2 (FDX2) competitively regulate mitochondrial iron–sulfur (Fe–S) cluster biosynthesis through their binding to the cysteine desulfurase NFS1 and the iron-sulfur cluster scaffold protein ISCU2 complex. Here, we discuss the potential of rationally designed peptide inhibitors targeting the FDX2–NFS1 interaction as a strategy to mitigate FXN deficiency and restore Fe–S cluster biosynthesis.