Osteosarcoma (OS) is the most frequent primary malignant bone
tumor. Ferroptosis, a form of regulated cell death, is a key
tumor suppression mechanism. Although
methionine adenosyltransferase II alpha (MAT2A) has been reported to inhibit several
tumor cells, it is unclear whether inhibition of MAT2A in OS cells can reduce ferroptosis.
CCK-8, flow cytometry, and Transwell assays were performed to evaluate cell viability, cell apoptosis/cycle, and cell migration, respectively. The levels of ferrous
iron and
glutathione (GSH) levels in cells were measured to evaluate the degree of cell ferroptosis. Western blot analysis was performed to detect
protein levels of MAT2A, p-STAT3 (Ser727)/STAT3, and solute carrier family 7 member 11 (SLC7A11) in OS cells. MAT2A was significantly upregulated in OS specimens and high MAT2A expression was associated with a poorer prognosis in OS patients.
shRNA targeting MAT2A significantly increased OS cell apoptosis, triggered cell cycle arrest in the G2 phase, and attenuated migration ability in vitro. MAT2A depletion dramatically inhibited
tumor progression of OS in vivo. Overexpression of MAT2A rescued the
tumor inhibition caused by miR-26b-5p. MAT2A knockdown promoted OS cell ferroptosis. miR-26b-5p/MAT2A regulates
tumor malignant progression and OS cell ferroptosis by controlling p-STAT3 and SLC7A11 expressions. Taken together, our study displayed that miR-26b-5p/MAT2A triggers ferroptosis in OS cells by increasing intracellular ferrous
iron levels and inhibiting the STAT3/SLC7A11 axis. Our results reveal a MAT2A-mediated ferroptosis defense mechanism used by OS cells and propose a potential ferroptosis-inducing strategy for the treatment of OS patients.