Major regulators of iron homeostasis include hepcidin, HIFs and IRP/IRE systems. [A] Hepcidin naturally limits the amount of iron efflux from cells and is inhibited by conditions such as anemia, hypoxia, increased testosterone, and increased erythropoiesis, while being upregulated by systemic iron overload and inflammation. [B] HIFs respond to low oxygen and iron levels and transcribe genes to help cells adapt to perceived environmental deficiencies for a more sustainable metabolism and long-term survival; this results in short- and long-term changes including increases in glycolysis, angiogenesis, iron supplies, and ultimately cell vitality. [C] IRPs control gene translation through binding of IREs on mRNA transcripts for iron metabolism-related proteins, either promoting translation through 3' UTR binding-dependent stabilization (e.g., TfR1, DMT1), or inhibiting translation through 5' UTR binding that results in eventual degradation (e.g., Ferritin, FPN). HIF: hypoxia-inducible factor; IRP: iron response protein; IRE: iron response element; mRNA: messenger RNA; UTR: untranslated region. Created with BioRender.com