IRX5 is a transcription factor that regulates energy homeostasis and skeletal development through multiple tissue-specific mechanisms. In adipose tissue, IRX5 suppresses mitochondrial thermogenesis by inhibiting beige adipocyte differentiation and promoting white adipocyte fate 1. Elevated IRX5 expression shifts energy metabolism toward storage rather than dissipation, with IRX5 knockdown in adipocytes increasing thermogenesis sevenfold 1. In bone, IRX5 functions in a dosage-dependent manner with IRX3 to promote osteogenesis while inhibiting adipogenesis in bone marrow 2. Mechanistically, IRX5 suppresses osteogenic differentiation by inhibiting mTOR-mediated ribosomal translation and mitochondrial oxidative phosphorylation 3. In the hypothalamus, IRX5 regulates postnatal neurogenesis in neural stem cells and modulates leptin sensing and feeding behavior 4, with IRX5 knockout mice showing increased basal metabolic rate and improved hypothalamic leptin response 5. IRX5 is a key mediator of FTO-associated obesity risk, where common variants regulate IRX5 expression across adipose and brain tissues during developmental windows 67. In Wilms tumor development, IRX5 promotes early proliferation in the nephrogenic blastema, distinguishing its function from IRX3 8.