Correlation between RNA N6-methyladenosine and ferroptosis in cancer: current status and prospects

Abstract

N⁶-methyladenosine (m⁶A) is the most abundant chemical modification in eukaryotic cells. It is a post-transcriptional modification of mRNA, a dynamic reversible process catalyzed by methyltransferase, demethylase, and binding proteins. Ferroptosis, a unique iron-dependent cell death, is regulated by various cell metabolic events, including many disease-related signaling pathways. And different ferroptosis inducers or inhibitors have been identified that can induce or inhibit the onset of ferroptosis through various targets and mechanisms. They have potential clinical value in the treatment of diverse diseases. Until now, it has been shown that in several cancer diseases m⁶A can be involved in the regulation of ferroptosis, which can impact subsequent treatment. This paper focuses on the concept, function, and biological role of m⁶A methylation modification and the interaction between m⁶A and ferroptosis, to provide new therapeutic strategies for treating malignant diseases and protecting the organism by targeting m⁶A to regulate ferroptosis.

Keywords: N6-methyladenosine; cancer; correlation; ferroptosis; regulation.

FIGURE 1

Summary of m⁶A modification machinery. The m⁶A methyltransferase complex composed of METTL3, METTL14, and WTAP, probably also of VIRMA and RBM15, serves as m⁶A “writer”, demethylases (FTO and ALKBH5) serve as m⁶A “erasers”. A set of m⁶A-binding proteins serve as m⁶A “readers” that determine the fate of target m⁶A-modified mRNA transcripts. Mature RNAs modified by m⁶A in the nucleus are recognized by readers, which subsequently mediate subcellular localization. In the cytoplasm, m⁶A is identified by cytoplasmic readers. It modulates RNA stability, translation, and binding capacity.

FIGURE 2

An overview of ferroptosis. An illustration demonstrating how intracellular and intercellular signaling events can influence ferroptosis by regulating cellular metabolism and ROS levels.

FIGURE 3

Mechanisms of m⁶A-modified ferroptosis pathways. m⁶A modification can change the metabolic course of ferroptosis in cells, regulate the changes of these factors, increase lipid peroxidation and iron accumulation in the tumor cell microenvironment, and thus inhibit the occurrence and development of tumors or reduce damage to the body.

FIGURE 4

m⁶A modification regulates the inhibition and occurrence of ferroptosis. As an inducer of modified regulated ferroptosis, m⁶A elucidated that exogenous drugs or high expression of m⁶A in tumors promoted ferroptosis and thus played an anticancer role. At the same time, m⁶A methylation regulates RNA, which can affect the drug resistance of some diseases, thus producing essential side effects for its treatment.