IARS2 encodes the mitochondrial isoleucyl-tRNA synthetase, an aminoacyl-tRNA synthetase essential for attaching isoleucine to its cognate tRNA during mitochondrial protein synthesis. Beyond its canonical translational role, IARS2 has emerged as a critical regulator of cellular proliferation and metabolic homeostasis across multiple cell types. In cancer biology, IARS2 is frequently upregulated and promotes tumor cell proliferation 12345. IARS2 knockdown consistently inhibits cell proliferation, induces G1 phase cell cycle arrest, and enhances apoptosis in melanoma, osteosarcoma, colon cancer, acute myeloid leukemia, and non-small cell lung cancer 12345. In endothelial cells, IARS2 regulates angiogenesis through ERK1/2 and protein kinase signaling pathways 6. Clinically, biallelic IARS2 mutations cause Leigh syndrome with combined mitochondrial complex I and III deficiencies, leading to impaired oxidative phosphorylation, reduced ATP production, and neurological manifestations 7. IARS2 mutations are also associated with craniosynostosis and abnormal genitalia syndrome 8. The discovery that IARS2 mutations compromise respiratory chain function reveals a pathogenic mechanism beyond simple translational defects, linking mitochondrial protein synthesis to oxidative energy metabolism.