Proposed luspatercept mechanism of action and outstanding questions. (A-B) Luspatercept’s proposed mechanism involves binding GDF11 and potentially other ligands, thereby preventing them from activating their endogenous receptors. The specific endogenous receptor(s) involved is currently unidentified but may be expressed on erythroid cells (C), cells within the bone marrow niche (D), or other cells (E). (F) The intracellular mechanisms by which luspatercept affects cell metabolism in both steady-state and ineffective erythropoiesis remain uncharacterized. Furthermore, how metabolism differentially modifies these 2 states of erythropoiesis is also unknown. The potential for luspatercept to modulate the activity of identical or other ligands and their receptors in other tissues (as shown in panel E), such as the liver and bone, has not yet been investigated. (G) Finally, whether luspatercept’s effects differ between young, growing patients and adults requires further evaluation. GDF11, growth differation factor 11.