Epigenetic Regulation and Nonepigenetic Mechanisms of Ferroptosis Drive Emerging Nanotherapeutics in Tumor

Abstract

Currently, traditional cancer therapy still falls far short of expectations. However, a variety of invasive cancers that are resistant to chemotherapy (such as platinum drugs, one of the most applied antineoplastics in clinic) and targeted agents are susceptible to ferroptosis. Ferroptosis is a form of cell death that is driven by cell metabolism and iron-dependent lipid peroxidation. Ferroptosis inducers can eliminate the drug resistance of tumor cells in the mesenchymal state, effectively inhibit the drug resistance of acquired tumor cells, and optimize cancer efficacy. Research based on the epigenetic mechanism of ferroptosis is still in the stage of screening and verifying the regulatory effect, and there is no complete regulatory mechanism network. In this review, we expound on the epigenetic regulation and nonepigenetic mechanisms of ferroptosis and review the epigenetic-based mechanisms of tumor therapy potential and emerging nonepigenetic-based therapies (nanotherapeutics).

Ferroptosis: A New Road towards Cancer Management

“…This interaction results in the formation of an intermediate between DPP4 and the nicotinamide adenine dinucleotide diphosphate oxidase-1 (NADPH Oxidase/NOX-1), that also accelerates the DPP4-dependent, plasma membrane-associated fatty acid peroxidation and, as a result, induces lipid peroxidation deposition and ferroptosis [ 87 ]. Furthermore, the p53 inhibition may limit the nuclear aggregation of DPP4 in CRC cells, while p53 overexpression results in DPP4 being concentrated in the nuclei and not binding to NOX1 [ 88 ]. Other studies imply that the p53-p21 transcriptional pathways may be involved in the regulation of ferroptosis in tumor cells that had lower ROS production and slower intracellular GSH depletion than normal cells [ 89 ].…”

“…Silencing of HSPA5 increases erastin-induced apoptosis in cells via the ferroptosis-dependent method [ 96 ]. The activating transcription factor-4 (ATF4) stimulates the production of HSPA5, which then in response interacts with Gpx4, resulting in the suppression of ferroptosis [ 88 ]. It is important to note that this ATF4-HSPA5-Gpx4 pathway, which mediates ferroptosis, also reduces the anticancer action of gemcitabine drugs [ 97 ].…”

The mechanisms of ferroptosis and its role in alzheimer’s disease

“…Nuclear receptor coactivator 4 (NCOA4) is a selective carrier receptor that can perform selective autophagy of ferritin (ferritinophagy) when intracellular iron levels are low so that iron is released (Ling et al, 2017). Arginine on the surface of the heavy ferritin chain FTH1 binds to a C-terminal domain of NCOA4 when iron levels are low, thereby promoting the transfer of autophagosomes to lysosomes (Mancias et al, 2015;Tang et al, 2018;Cheng et al, 2021). Mancias et al (2015).…”