Ferroptosis and EMT: key targets for combating cancer progression and therapy resistance

Abstract

Iron-dependent lipid peroxidation causes ferroptosis, a form of regulated cell death. Crucial steps in the formation of ferroptosis include the accumulation of ferrous ions (Fe2+) and lipid peroxidation, of which are controlled by glutathione peroxidase 4 (GPX4). Its crucial role in stopping the spread of cancer has been shown by numerous studies undertaken in the last ten years. Epithelial–mesenchymal transition (EMT) is the process by which epithelial cells acquire mesenchymal characteristics. EMT is connected to carcinogenesis, invasiveness, metastasis, and therapeutic resistance in cancer. It is controlled by a range of internal and external signals and changes the phenotype from epithelial to mesenchymal like. Studies have shown that mesenchymal cancer cells tend to be more ferroptotic than their epithelial counterparts. Drug-resistant cancer cells are more easily killed by inducers of ferroptosis when they undergo EMT. Therefore, understanding the interaction between ferroptosis and EMT will help identify novel cancer treatment targets. In-depth discussion is given to the regulation of ferroptosis, the potential application of EMT in the treatment of cancer, and the relationships between ferroptosis, EMT, and signaling pathways associated with tumors. Invasion, metastasis, and inflammation in cancer all include ferroptosis and EMT. The goal of this review is to provide suggestions for future research and practical guidance for applying ferroptosis and EMT in clinical practice.

Transcriptome exploration of ferroptosis-related genes in TGFβ- induced lens epithelial to mesenchymal transition during posterior capsular opacification development

“…Research also indicates that ferroptosis can directly increase the expression of COX2 and enhance the secretion of inflammatory signals. Inflammatory compounds stimulate late-stage transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and ZEB promoting EMT [ 38 ]. Studies has shown that TGF-β promotes the expression of NOX4 in rat LECs and inhibition of NOX4 can block the EMT process [ 39 , 40 ], also DAS et al [ 41 ] proposed that the deletion of NOX4 is in both in vitro and in vivo only a partial repeal of the EMT response, which it was clear that other sources of reactive oxygen species (ROS) have an impact in the EMT process of LECs.…”

Ferroptosis: Emerging mechanisms, biological function, and therapeutic potential in cancer and inflammation

“…Further, the inclusion of HIF while inhibiting GPX4 mitigates GPX4-mediated ferroptosis. HIF-1α and HIF-2α have been identified as regulators of ferroptosis in renal clear cell carcinoma cells [ 107 ]. Inducing the expression of HIF-1α through increasing the expression of fatty acid-binding proteins 3 and 7 under hypoxic conditions inhibits ferroptosis [ 108 ].…”

Ferroptosis and EMT resistance in cancer: a comprehensive review of the interplay

“…Highly mesenchymal stem cells confer drug-resistant properties to different cancer types. A growing body of clinical evidence suggests that targeting ferroptosis holds promise as a potential strategy to overcome drug resistance and augment the therapeutic effectiveness of anticancer treatments ( 12 ). Ferroptosis inducers demonstrate the ability to reverse acquired resistance in cancer cells to various anticancer agents such as lapatinib, cisplatin, docetaxel, sorafenib, among others.…”