NFS1 as a Metabolic Vulnerability in Acute Myeloid Leukemia Through Iron Dysregulation and STAT1/IFIT2-Associated Signaling.

Acute myeloid leukemia (AML) is a metabolically heterogeneous malignancy with poor outcomes and limited durable therapeutic options. We investigated NFS1, a key enzyme involved in iron-sulfur cluster biogenesis, as a potential metabolic vulnerability in AML. NFS1 was overexpressed in AML samples, and higher expression was associated with inferior overall survival in the TCGA-LAML cohort. Genetic knockdown of NFS1 markedly suppressed AML cell proliferation in vitro and reduced tumor growth in subcutaneous xenograft models. NFS1 knockdown induced disturbances in iron homeostasis accompanied by increased reactive oxygen species production and lipid peroxidation, together with reduced GPX4 expression. Together with the partial restoration of cell viability by ferrostatin-1, deferoxamine, and Z-VAD-FMK, these changes were consistent with concurrent apoptotic and ferroptosis-like cell death. Transcriptomic analysis revealed enrichment of type I interferon-related signaling pathways, while experimental validation demonstrated increased STAT1 phosphorylation at Tyr701 and increased expression of the downstream effector IFIT2. IFIT2 knockdown partially reversed the anti-proliferative effects of NFS1 knockdown, supporting an association between the growth-suppressive phenotype induced by NFS1 knockdown and STAT1/IFIT2-associated signaling. NFS1 knockdown was also accompanied by increased expression of PD-L1 and elevated concentrations of inflammatory cytokines such as IL-6 and IL-8, and reduced CD80 expression in THP-1-derived macrophage-like cells in an in vitro co-culture system. These findings indicate that NFS1 depletion is associated with immune-related transcriptional and phenotypic changes in vitro. Furthermore, NFS1 knockdown enhanced the in vitro sensitivity of AML cells to azacitidine, venetoclax, and bortezomib. Collectively, this study suggests that NFS1 may represent a metabolic vulnerability in AML that links its depletion to iron dysregulation, apoptotic and ferroptosis-like cell death, and STAT1/IFIT2-associated signaling, providing a rationale for further investigation of NFS1 as a potential therapeutic target in AML.