Gastric cancer (GC) remains the leading cause of cancer deaths worldwide. GC development is a multistep and multifactorial process, and the molecular characterization of the multistage progression of gastric lesions to GC is poorly understood. Induction of ferroptosis driven by iron-dependent phospholipid peroxidation ameliorates the malignant progression of GC. Here, we found that solute carrier family 47 member 1 (SLC47A1) promoted GC progression by regulating ferroptosis. Clinically, SLC47A1 was elevated during the progression of gastritis to GC, and its high expression was associated with poor prognosis in patients with GC. Knockdown of SLC47A1 significantly inhibited cell proliferation, colony formation, and tumor growth. Further studies revealed that SLC47A1 was a regulator of ferroptosis rather than apoptosis or necrosis. Knockdown of SLC47A1 promoted ferroptosis in GC cells, as evidenced by increased erastin-induced cytoplasmic membrane rupture, cell death, lipid peroxidation, and malondialdehyde levels. Mechanistically, GATA6 promoted SLC47A1 transcription, leading to elevated SLC47A1 expression and promoting ferroptosis in GC cells. In summary, our study revealed the significant role of SLC47A1 in the development and progression of GC through regulating ferroptosis. Targeting the GATA6/SLC47A1 axis may be a promising therapeutic strategy for GC.
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