Critical role of non-coding RNA-mediated ferroptosis in urologic malignancies

Abstract

Urologic malignancies, characterized by their high aggressiveness and metastatic potential, pose a significant public health challenge globally. Ferroptosis, a novel mode of cell death, typically arises from intracellular iron ion overload and the accumulation of lipid peroxides. This process has been shown to play a crucial regulatory role in various pathological conditions, particularly in cancer, including urologic cancers. However, the comprehensive regulatory mechanisms underlying ferroptosis remain poorly understood, which somewhat limits its broader application in cancer therapy. Non-coding RNAs (ncRNAs), which encompass microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are non-coding transcripts that play pivotal roles in various physiological processes, such as proliferation, differentiation, apoptosis, and cell cycle regulation, by modulating the expression of target genes. The biological functions and potential regulatory mechanisms of ncRNAs in the context of cancer-related ferroptosis have been partially elucidated. Research indicates that ncRNAs can influence the progression of urologic cancers by affecting cell proliferation, migration, and drug resistance through the regulation of ferroptosis. Consequently, this review aims to clarify the functions and mechanisms of the ncRNA-ferroptosis axis in urologic cancers and to evaluate the clinical significance of ferroptosis-related ncRNAs, thereby providing new insights into cancer biology and therapeutic strategies that may ultimately benefit a diverse range of cancer patients.

Keywords: circRNA; ferroptosis; lncRNA; miRNA; molecular mechanism; urologic malignancy.

Figure 1

Ferroptosis signaling pathway. Ferroptosis is primarily regulated by iron metabolism, amino acid metabolism, and lipid metabolism. Initially, extracellular iron ions bind to TF/TFRC, subsequently entering the cytoplasm to form endosomes. These ions then enter the labile iron pool (LIP) via the actions of STEAP3 metal reductase and DMT1. Ferritin regulates the content of the LIP through autophagy or storage, whereas excess iron ions are expelled from cells via SLC40A1. The Fenton reaction involving Fe²⁺ and hydrogen peroxide generates reactive oxygen species (ROS), which promote ferroptosis. Secondly, cystine enters the cell via System Xc^- and is converted to glutathione (GSH) through reduction and enzymatic reactions. The GSH-GPX4 axis functions as an antioxidant defense system in vivo, inhibiting ferroptosis. Lastly, polyunsaturated fatty acids (PUFA) in lipids are enzymatically converted into PL-PUFA-OOH, promoting ferroptosis. Additionally, the FSP1-CoQ10-NAD(P)H, PPR11-DHODH, and GCH1-BH4 pathways also regulate ferroptosis.

Figure 2

Critical role of the ncRNA-ferroptosis axis in urologic cancers. MicroRNAs (miRNAs) influence ferroptosis in urologic cancers by regulating genes associated with ferroptosis. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) regulate ferroptosis primarily by targeting specific microRNAs (miRNAs) through a sponge effect.