Circular RNA TFRC/SCD1 mRNA interaction regulates ferroptosis and metastasis in gastric cancer

Abstract Ferroptosis, an iron-dependent form of programmed cell death, holds promise for cancer treatment. Circular RNAs (circRNAs), widely expressed across tumor types, modulate multiple cellular biological processes, including ferroptosis. However, the regulatory dynamics of circRNAs in gastric cancer (GC)-associated ferroptosis remain poorly understood. Here, circTFRC (circBase ID: hsa_circ_0068606), a novel circRNA, was identified as significantly upregulated in GC tissues and cell lines, with its plasma levels strongly associated with tumor size and metastatic status. Targeted suppression of circTFRC enhanced ferroptotic cell death, resulting in reduced proliferation and motility of GC cells in vitro. At the molecular level, circTFRC bound directly to SCD1 mRNAs, stabilizing and enhancing their translation via recruiting the RNA-binding protein ELAVL1. Elevated SCD1 expression mitigated ferroptosis and promoted oncogenic lipid metabolic reprogramming, thereby driving GC progression. In vivo studies further confirmed that circTFRC silencing promoted ferroptosis and inhibited tumor growth and progression. These results delineate a circTFRC-mediated axis that impairs ferroptosis vulnerability in GC cells and supports malignancy advancement. CircTFRC emerges as a biomarker with diagnostic potential and a candidate for therapeutic intervention targeting ferroptosis in GC.