IRX3 (iroquois homeobox 3) is a transcription factor with critical roles in energy metabolism, neural development, and cardiac conduction system regulation. In energy homeostasis, IRX3 acts as a key mediator of obesity risk through the FTO locus, where genetic variants lead to increased IRX3 expression during adipocyte differentiation 1. This elevation causes a developmental shift from energy-dissipating beige adipocytes to energy-storing white adipocytes, reducing mitochondrial thermogenesis and increasing lipid storage 1. IRX3 regulates this process by modulating SUMOylation pathways and chr16 remodeling, with over 300 binding sites identified at genes involved in these processes 2. In neural development, IRX3 functions as a genetic determinant regulating neurogenic properties of radial glia-like neural stem cells in postnatal hypothalamic neurogenesis, contributing to energy homeostasis regulation 3. Additionally, IRX3 plays a role in cardiac conduction system development, where it works with TBX3 to establish region-specific gene regulatory networks across different cardiac conduction components 4. Recent evidence also implicates IRX3 in glioblastoma progression through activation of Wnt/β-catenin signaling 5, highlighting its diverse regulatory functions across multiple physiological systems.