Insights into the Roles of Epigenetic Modifications in Ferroptosis

Abstract

Ferroptosis is a non-apoptotic mode of cell death driven by membrane lipid peroxidation and is characterized by elevated intracellular levels of Fe²⁺, ROS, and lipid peroxidation. Studies have shown that ferroptosis is related to the development of multiple diseases, such as cancer, neurodegenerative diseases, and acute myeloid leukemia. Ferroptosis plays a dual role in the occurrence and development of these diseases. Ferroptosis mainly involves iron metabolism, ROS, and lipid metabolism. Various mechanisms, including epigenetic regulation, have been reported to be deeply involved in ferroptosis. Abnormal epigenetic modifications have been reported to promote tumor onset or other diseases and resistance to chemotherapy drugs. In recent years, diversified studies have shown that epigenetic modification is involved in ferroptosis. In this review, we reviewed the current resistance system of ferroptosis and the research progress of epigenetic modification, such as DNA methylation, RNA methylation, non-coding RNAs, and histone modification in cancer and other diseases by regulating ferroptosis.

Keywords: DNA methylation; RNA methylation; epigenetic modification; ferroptosis; histone modification; non-coding RNA.

Figure 1

The figure is created via the biorender application, (BioRender.com, accessed on 24 December 2023). Core mechanisms of ferroptosis. The iron-dependent peroxidation of PUFA-PLs is central to ferroptosis. At least four ferroptosis-resistant systems have been identified in cells, including the GPX4/xCT system, the FSP1/CoQH2 system, the DHODH/CoQH2 system, and the GCH1/BH4 system, which prevent lipid peroxidation in different subcellular localizations, thereby protecting cells from ferroptosis. ACSL4 and LPCAT3 are engaged in the synthesis of PUFA-PLs. Iron initiates the Fenton reaction with H₂O₂ and is an important cofactor for ALOXs (arachidonate lipoxygenases) and POR (cytochrome P450 reductase), promoting lipid peroxidation. Once the induction of ferroptosis significantly exceeds the detoxification capacity of the ferroptosis-resistant system, the accumulation of lipid peroxides on cell membranes leads to membrane rupture and triggers ferroptosis.

Figure 2

The regulation of ferroptosis by DNA and RNA methylation. (A) DNA methylation in ferroptosis. LSH interacts with WDR76 and inhibits ferroptosis through affecting the DNA methylation of FADS2, SCD1, and GLUT1. DNMTs including DNMT1, DNMT3A, and DNMT3B usually inhibit the expression of target genes to regulate ferroptosis. Inversely, the DNMT inhibitor 5-Aza antagonizes the biological function of DNMTs. (B) RNA m6A modification in ferroptosis. METTL3 increases the m6A modification of SLC7A11 and FSP1 RNA. YTHDC2 acts as a SLC7A11 and FSP1 mRNA reader, leading to mRNA decay to induce ferroptosis. IGF2BP1 acts as a SLC7A11 mRNA reader and increases its translation to inhibit ferroptosis. FTO inhibits the m6A modification of GPX4 mRNA. YTHDF2 acts as a GPX4 mRNA reader, resulting in mRNA decay to induce ferroptosis. The dotted line represents indirect regulation.

Figure 3

The regulation of ferroptosis by NcRNAs. NcRNAs target metabolizable molecules such as ACSL4 and ALOX15 in lipid metabolism to regulate ferroptosis. NcRNAs regulate ferroptosis in classical and non-classical signaling pathways, such as the p53/NRF2-SLC7A11-GPX4 axis and GCH1. NcRNAs target iron-related proteins such as FTH1 [104], TFRC [105], and IREB2 [106], and regulate ferroptosis in iron metabolism.

Figure 4

The regulation of ferroptosis by histone modification. (A) Histone acetylation in regulating ferroptosis. JQ1 and ketamine-induced ferroptosis by reducing the H3K27ac level of the BRD4 and GPX4 genes, respectively. PCAF inhibited ferroptosis by promoting the H3K27ac level of the NRF2 gene. (B) Histone methylation in regulating ferroptosis. KDM4A and KDM3B decrease the H3K9me3 and H3K9me1/2 levels of the SLC7A11 gene to inhibit ferroptosis. G9a promotes the H3K9me2 level of the GPX4 gene to induce ferroptosis.