SFXN4 (sideroflexin 4) is a mitochondrial inner membrane transporter belonging to the SLC56 family that plays a critical role in iron-sulfur (Fe-S) cluster biogenesis and mitochondrial iron homeostasis 1. Unlike other family members SFXN1 and SFXN3, SFXN4 does not function as a serine transporter but instead facilitates mitochondrial iron regulation 1. SFXN4 is essential for maintaining Fe-S cluster stability and availability to respiratory complexes; its loss impairs mitochondrial respiration and shifts metabolism toward glycolysis 2. SFXN4 knockdown also affects heme biosynthesis by reducing ferrochelatase and ALAS2 translation, while redistributing iron from cytosol to mitochondria via the aconitase-IRP1 switch 2. Clinically, biallelic SFXN4 mutations cause combined oxidative phosphorylation deficiency presenting as mitochondrial disease with macrocytic anemia and megaloblastic features 3. Prenatal presentations include intrauterine growth retardation, neonatal lactic acidosis, complex I deficiency, and optic nerve hypoplasia 4. Beyond monogenic disease, SFXN4 dysregulation associates with cancer progression: elevated SFXN4 promotes osteosarcoma and hepatocellular carcinoma cell growth, migration, and invasion 56. In ovarian cancer, SFXN4 inhibition synergistically sensitizes resistant cells to DNA-damaging chemotherapy and PARP inhibitors by simultaneously impairing Fe-S-dependent DNA repair and inducing oxidative stress 7.