Long non-coding RNA ZFAS1 promotes ferroptosis by regulating the miR-185-5p/SLC25A28 axis in clear cell renal cell carcinoma

Ferroptosis is a novel, iron-dependent regulated cell death mode. The biochemical features of ferroptosis include iron accumulation, lipid peroxidation, inhibition of glutathione peroxidase 4 (GPX4) and antioxidant glutathione (GSH) decrease through inhibition of the system xc^- transporter. Zinc finger NFX1 type-containing 1 (ZNFX1) antisense RNA 1 (ZFAS1) is a long non-coding RNA that has been identified as an oncogene in various types of cancers. However, its regulatory role and molecular mechanisms in clear cell renal cell carcinoma (ccRCC) ferroptosis remain unclear. In this study, the ferroptosis inducers (FINS) (erastin and RSL3) were found to increase ZFAS1 expression through the facilitation of SP1 binding to the ZFAS1 promoter. ZFAS1 increased mRNA and protein levels of solute carrier family 25 member 28 (SLC25A28) via functioning as a miR-185-5p sponge. Overexpressed SLC25A28 increased the production of ROS and caused a decrease in NADPH and GSH in cells treated with FINS. In addition, overexpression of ZFAS1 enhanced ferroptosis both in vitro and in vivo. Altogether, this study demonstrates that ZFAS1 is a crucial element of ferroptosis in ccRCC, as it is responsible for the regulation of miR-185-5p and SLC25A28. Introducing ferroptosis could be a beneficial approach to treat ccRCC patients with high ZFAS1 levels.