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Inhibition of GOT1 Potentiates Ferroptosis and Exacerbates Cell Death in Acute Myeloid Leukemia

ABSTRACT: Background Drug resistance, poor treatment response, and low long-term survival rates are major obstacles to the successful long-term treatment of acute myeloid leukemia (AML), a heterogeneous hematologic malignancy. A deeper understanding of the molecular mechanisms underlying AML is therefore essential. GOT1, a key metabolic enzyme, has emerged as a potential regulator of AML progression, though its precise role remains unclear. This study aimed to investigate the expression profile, function significance, and mechanistic involvement of GOT1 in AML. Methods The expression levels of GOT1 in AML patient samples and cell lines were quantified by RT-qPCR. Genetic knockdown (shRNA) and pharmacological inhibition (compound 2C) were employed to suppress GOT1 activity. Functional assays, including CCK-8 assay and Annexin V/PI staining, evaluated proliferation and apoptosis of AML cells. Multi-omics analyses (transcriptomics, proteomics, and metabolomics) were performed to delineate the mechanistic landscape of GOT1 inhibition. Reactive oxygen species levels in AML cells treated with compound 2C were measured by flow cytometry. The combined effects of compound 2C and ferroptosis inducers (RSL3/FIN56) were evaluated using the CCK-8 assay. Results The expression of GOT1 was significantly upregulated in AML patients and cell lines compared to controls. Inhibition of GOT1 suppressed AML proliferation and induced cell death via triggering ferroptosis. Multi-omics profiling revealed perturbations in redox homeostasis and iron metabolism pathways upon GOT1 suppression. Notably, GOT1 inhibition (compound 2C) combined with ferroptosis inducers (RSL3/FIN56) synergistically reduced AML cell viability. Conclusion Our findings demonstrate that GOT1 drives AML progression by modulating ferroptosis susceptibility. Targeting GOT1, either alone or in combination with ferroptosis inducers, represents a novel therapeutic strategy to overcome resistance and improve outcomes in AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315382 | GEO | 2026/06/30

REPOSITORIES: GEO

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Project description:Background/Objectives: Ferroptosis, an iron-dependent form of cell death, shows promise as a target for therapy-resistant cancers that exhibit increased iron metabolism. Ferroptosis is primarily characterised by lipid peroxidation within cell membranes. However, many cancers evade ferroptosis by upregulation of specialised ferroptosis defence mechanisms. This study investigates ferroptosis susceptibility in Tuberous Sclerosis Complex (TSC) cell models, and ovarian and breast cancer cell lines to identify ferroptosis resistance mechanisms and therapeutic targets. Methods: We assessed ferroptosis susceptibility using the ferroptosis inducers, RSL3 and erastin. We explored ferroptosis resistance genes using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA-sequencing was conducted to identify dysregulated ferroptosis resistance genes and to better characterise NRF2 target genes. RNA sequencing was also performed to identify gene expression after treatment with pro-ferroptotic iron-oxide nanoparticles. Results: TSC2-deficient cells exhibited resistance to RSL3 and erastin-induced ferroptosis, which correlated with increased ferroptosis defence gene expression, including NRF2 and downstream targets. NRF2 inhibition re-sensitised TSC2-deficient cells to ferroptosis, confirming its protective role. However, FSP1 inhibition did not re-sensitise TSC2-deficient angiomyolipoma kidney tumor cells to RSL3. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cell lines. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition in reversing ferroptosis resistance. Conclusions: Our findings highlight NRF2 and FSP1 as key regulators of ferroptosis resistance in TSC2-deficient and cancer cells. However, the differential efficacy of targeting these pathways suggests that patient stratification may be necessary for optimal therapeutic strategies. Targeting NRF2 and FSP1 could enhance ferroptosis susceptibility, offering a potential therapeutic approach for ferroptosis resistance cancers.

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Inhibition of GOT1 Potentiates Ferroptosis and Exacerbates Cell Death in Acute Myeloid Leukemia

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