Inhibition of nucleoporin 214 depletes leukemia stem cells by promoting heme catabolism and lipid peroxidation.

NUP214 overexpression is a critical fitness determinant in acute myeloid leukemia leukemia stem cells, and its inhibition triggers ferroptosis via heme catabolism and lipid peroxidation.

• Why it matters: Wild-type nucleoporin functions in AML are largely unknown despite recurrent NUP chromosomal translocations, limiting targeted strategies against leukemia stem cells.
• What they did: The authors screened the NUP family, then used NUP214 deficiency and a selective NUP214 degrader, 0449-b, to assess heme catabolism, Fe²⁺ accumulation, lipid peroxidation, and ferroptosis.
• The result: NUP214 loss upregulates HMOX1 and ALOX15, causing heme exhaustion and excessive lipid peroxidation that triggers ferroptosis and impairs AML progression, while 0449-b shows anti-leukemic activity in vivo sparing normal hematopoietic stem cells.

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