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

Abstract

Chromosomal translocations involving nucleoporin (NUP) loci, such as NUP98 and NUP214, are recurrent in acute myeloid leukemia (AML). However, the intrinsic functions of wild-type nucleoporins in AML remain largely unknown. By screening the NUP family, we identified NUP214 as a frequently overexpressed gene and a critical fitness determinant in leukemia stem cells (LSCs). NUP214 acts as a conserved driver of LSC survival by restricting heme catabolism, limiting Fe²⁺ accumulation, and suppressing lipid peroxidation. Conversely, NUP214 deficiency leads to upregulation of heme oxygenase 1 (HMOX1) and arachidonate 15-lipoxygenase (ALOX15), causing heme exhaustion and excessive lipid peroxidation, which ultimately triggers ferroptosis in LSCs and impairs AML progression. Mechanistically, NUP214 translocates into the nucleoplasm where it blocks Sub1-mediated RNA polymerase II recruitment to repress transcription of the key pro-ferroptotic genes HMOX1 and ALOX15, revealing a non-canonical role beyond its nuclear pore function. Furthermore, we developed the small-molecule compound 0449-b, which acts as a selective NUP214 degrader by recruiting NUP214 to the Cullin5-Rbx2 E3 ligase complex, inducing its neddylation and proteasomal degradation. 0449-b potently triggers LSC ferroptosis and exhibits anti-leukemic activity in vivo, while sparing normal hematopoietic stem cells. Collectively, our findings establish NUP214 as a critical oncoprotein that orchestrates heme metabolism and lipid peroxidation to sustain LSCs, and highlight NUP214-targeted degradation as a promising intervention strategy for AML.