HIF3A encodes a hypoxia-inducible transcription factor that functions as a negative regulator of HIF1A-driven gene expression. HIF3A attenuates HIF1A's ability to bind hypoxia-responsive elements (HREs) in enhancer/promoter regions, thereby inhibiting HRE-driven transcriptional activation [UniProt annotation]. During sustained hypoxia, HIF3A expression increases while HIF1A decreases, mediated by miR-429, establishing a regulatory switch from adaptive HIF-1 responses to HIF-3 survival responses 1. HIF3A protects against ferroptosis through the HIF-3α-GPx4 axis; HIF-3α downregulation in alveolar epithelial cells contributes to COPD pathogenesis, while HIF-3α overexpression prevents emphysema and lung function decline 2. In metabolic disease, HIF3A DNA methylation associates with obesity, weight gain, and insulin resistance; notably, reduced HIF3A expression in subcutaneous adipose tissue correlates with decreased insulin sensitivity 3. HIF3A inhibition promotes browning of white adipocytes through upregulation of thermogenic genes (Ucp1, Prdm16, Dio2, Ppargc1a), enhancing mitochondrial uncoupling and metabolic rewiring with therapeutic potential for obesity and type 2 diabetes 4. Elevated HIF3A methylation associates with increased breast cancer risk 5. These findings establish HIF3A as a multifunctional regulator of oxygen homeostasis, metabolic health, and disease prevention.