Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Abstract

Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other cell death modes, plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications and posttranslational modifications (PTMs) promote anticancer drug resistance, cancer progression, and metastasis. Accumulating studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases (NSDs), cardiovascular diseases (CVDs), liver diseases, lung diseases, and kidney diseases. In this review, we first summarize the core molecular mechanisms of ferroptosis. Then, the roles of epigenetic processes, including histone PTMs, DNA methylation, and noncoding RNA regulation and PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, and ADP-ribosylation, are concisely discussed. The roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases, including cancers, NSD, CVDs, liver diseases, lung diseases, and kidney diseases, as well as the application of epigenetic and PTM modulators in the therapy of these diseases, are then discussed in detail. Elucidating the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other diseases. In addition, these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

Insights into the Roles of Epigenetic Modifications in Ferroptosis

“…The current mechanism of RNA methylation regulating ferroptosis is mainly focused on the classical SLC7A11-GPX4 axis, and RNA methylation modifications in non-classical ferroptosis regulatory mechanisms need to be further investigated. An increasing number of epigenetic modifications that induce or inhibit ferroptosis targets are being identified, and combinations of epigenetic drugs with other conventional therapies are used in preclinical studies and clinical testing [12]. MiR-101-3p and E/M@FA-LP nanomedicines have promising antitumor effects in treating ferroptosis-associated tumors [108,143].…”

“…MiR-101-3p and E/M@FA-LP nanomedicines have promising antitumor effects in treating ferroptosis-associated tumors [108,143]. However, the modulation of ferroptosis through treatment with the same epigenetic modifications may show opposite effects in different tissues or diseases [12,50]. Epigenetic factors involve the development and progress of cancer and other diseases by regulating ferroptosis-associated genes.…”

“…Vitamin E was shown to rescue the Gpx4deficient hematopoietic stem and progenitor cells from ferroptosis in vitro [8]. In addition to the classical SLC7A11-GPX4 axis, four additional mechanisms have been identified to be involved in the regulation of ferroptosis: the FSP1/ubiquinone (CoQ10)/NADPH pathway [9], the GTP cyclohydrolysate 1 (GCH1)/tetrahydrobiopterin (BH4) pathway [10], the dihydroorotate dehydrogenase (DHODH) pathway [11], and the O-acyltransferase 1/2 (MBOAT1/2)-monounsaturated fatty acid (MUFA) system [12]. It has been shown that ferroptosis is widespread in humans, mammals, plants, protists, and fungi [13].…”

Targeting tumor suppressor p53 for organ fibrosis therapy

“…The activation of HSCs is a central event during hepatic fibrosis. Ferroptosis is a new type of iron-dependent non-apoptotic cell death, inhibition of p53-mediated HSC ferroptosis has been shown to promote hepatic fibrosis by triggering ECM deposition and HSC activation [ 89 – 91 ]. Lujambio et al found that in CCl4-treated mice, HSC-specific deletion of p53 exhibits an excessive accumulation of collagen production and an overall decreased senescent HSCs, indicating that p53 accumulation in HSCs can ameliorate hepatic fibrosis by promoting HSC senescence [ 92 ].…”

Ferroptosis in liver cancer: a key role of post-translational modifications

“…Abnormal PTMs can lead to changes in protein properties and loss of protein function. These changes are closely associated with the development and progression of many diseases ( 23 ). The PTM of a variety of proteins (e.g., Phosphorylation, ubiquitination, acetylation, and methylation) also plays an integral regulatory role in ferroptosis ( 24 ).…”