The Regulation of Ferroptosis by circRNAs in Various Cancers.

Abstract

Ferroptosis, an iron-dependent and lipid-peroxidation-driven form of regulated cell death, has emerged as a central hub linking tumour initiation, metastatic spread, and resistance to radiotherapy and chemotherapy. At its core, labile Fe²⁺, which is imported via the transferrin/transferrin receptor axis, fuels Fenton chemistry by generating hydroxyl rad-icals that oxidise polyunsaturated fatty acids in membrane phospholipids. Cellular survival is heavily dependent on the system Xc⁻ antiporter, which imports cystine for glutathione (GSH) synthesis and thereby sustains glutathione peroxidase 4 (GPX4)-mediated detoxifi-cation of lipid peroxides. The collapse of this process precipitates ferroptosis, a form of reg-ulated cell death. Circular RNAs (circRNAs), defined as covalently closed, highly stable transcripts, have recently been identified as post-transcriptional regulators of this lethal cas-cade. By acting as effective 'sponges' for microRNAs, they effectively de-repress critical nodes of iron homeostasis, lipid remodelling, and ROS clearance. Select circRNAs have been observed to physically interact with GPX4 or Beclin-1, thereby either restraining or amplifying ferroptotic signalling. Consequently, circRNAs reprogramme the ferroptosis landscape of cancer cells, influencing proliferation, invasion, and therapy response. In this study, we synthesise and critically evaluate the current evidence for circRNA-mediated con-trol of ferroptosis across human malignancies. We also outline how circRNA silencing, over-expression, or genome editing could be exploited to synchronise iron depletion with conven-tional cytotoxic drugs. This offers a rational avenue to overcome chemo- and radio-re-sistance.