This figure illustrates the hypothesis of Egan et al¹  and may be applied analogously to other erythropoietic porphyrias. (Left) A normal to increased iron availability is shown. Thereby, IRP2 is ubiquinated and destroyed, likely by an action of the iron-sensing protein “F-box and leucine-rich repeat protein 5.” IRE in the 5′ end of ALAS2 is unbound, and translation of ALAS2 protein proceeds. This leads to increased activity of this enzyme, controlling the rate of erythropoietic heme synthesis, and an increased overflow of porphyrin intermediaries such as uroporphyrin I in CEP. In CEP, the bottleneck of heme synthesis is the activity of the enzyme uroporphyrinogen III synthase (UROS), whereas in other erythropoietic porphyrias, other enzymes represent the bottlenecks, such as uroporphyrinogen decarboxylase in hepatoerythropoietic porphyria or ferrochelatase in erythropoietic protoporphyria. As shown by Barman-Aksözen et al,⁶  decreased heme synthesis increases ALAS2 activity by a yet-unknown mechanism. (Right) In an iron-deprived situation, IRP2 is active, binds to the IRE, and blocks ALAS2 translation. As less porphyrin intermediaries are synthesized, their overflow at the bottleneck of UROS is diminished, which reduces symptoms and improves survival of erythrocyte precursor cells in bone marrow. Similar effects of iron deprivation can be expected in other erythropoietic porphyrias. Professional illustration by Luk Cox, Somersault18:24.