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

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.