Abstract

Solute carrier family 1 member 1 (SLC1A1, also known as excitatory amino acid transporter 3) is a member of the EAAT family of sodium-dependent glutamate carriers. Ferroptosis is a nonapoptotic cell death that is caused by phospholipid peroxidation promoted by radical reactions involving iron. Here, we identify SLC1A1 as a driver of ferroptosis resistance in PDAC cells and delineate the cause of its upregulation. SLC1A1 was overexpressed in PDAC tumors and correlated with poorer prognosis. Knockdown of SLC1A1 reduced cystine uptake by inhibiting glutamate transport, leading to decreased cysteine, GSH, and glutathione peroxidase 4 (GPX4) content, and the production of ROS and lipid peroxidation. Knockdown of SLC1A1 enhanced the ferroptosis sensitivity of PDAC cells and promoted ferroptosis inducer RSL3-induced ferroptosis and tumor suppression. Long noncoding RNA RASSF1-AS1 bound to CCCTC-binding factor (CTCF) protein, thereby inhibiting CTCF-mediated SLC1A1 transcription. Overexpression of RASSF1-AS1 enhanced the ferroptosis sensitivity of PDAC by blocking glutamate transport in vitro and in vivo, which was reversed by restoring CTCF/SLC1A1 signaling. Taken together, RASSF1-AS1 enhances the ferroptosis sensitivity of PDAC by inhibiting the CTCF/SLC1A1 axis-mediated intracellular transport of glutamate.