Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers

Abstract

Ferroptosis is a novel form of non-apoptotic regulated cell death (RCD), with distinct characteristics and functions in physical conditions and multiple diseases such as cancers. Unlike apoptosis and autophagy, this new RCD is an iron-dependent cell death with features of lethal accumulation of reactive oxygen species (ROS) and over production of lipid peroxidation. Excessive iron from aberrant iron metabolisms or the maladjustment of the two main redox systems thiols and lipid peroxidation role as the major causes of ROS generation, and the redox-acrive ferrous (intracellular labile iron) is a crucial factor for the lipid peroxidation. Regulation of ferrroptosis also involves different pathways such as mevalonate pathway, P53 pathway and p62-Keap1-Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. Ferroptosis roles as a double-edged sword either suppressing or promoting tumor progression with the release of multiple signaling molecules in the tumor microenvironment. Emerging evidence suggests ferroptosis as a potential target for cancer therapy and ferroptosis inducers including small molecules and nanomaterials have been developed. The application of ferroptosis inducers also relates to overcoming drug resistance and preventing tumor metastasis, and may become a promising strategy combined with other anti-cancer therapies. Here, we summarize the ferroptosis characters from its underlying basis and role in cancer, followed by its possible applications in cancer therapies and challenges maintained.

Keywords: Cancer; ferroptosis; immune; tumor microenvironment.

Figure 1

Mechanisms of ferroptosis. Mechanisms of Ferroptosis. Excess irons are regarded as an important factor for ferroptosis. The circulated iron (Fe³⁺) combined with transferrin (TF) enters into cells mediated by transferrin receptor (TFR). Under the catalysis of iron oxide reductase STEAP3, Fe³⁺ can be deoxidized to Fe²⁺ and ultimately, releasing it into labile iron pool (LIP) mediated by DMT1. LIP consists of iron from endosomal uptake of circulated iron and ferritin degradation (ferritinophagy). System Xc-mediate the uptake of cystine (Cys2). Cys2, glutamate (Glu) and glycine (Gly) are materials of glutathione (GSH), which is an important antioxidant in cells. Transsulfurylation pathway may also increase the level of cysteine transformed from methionine (Met). Cysteine can be imported directly by alanine/serine/cysteine transporter (system ASC) under reducing conditions. The uptake of free PUAs such as arachidonic acid (AA) or adrenoxyl (AdA) mediated by fatty acid translocase (FAT) and fatty acid transport protein (FATP) can be converted to membrane phospholipids by enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), which is important to ROS generation. PE-PUFAs can be oxidized to PE-PUFAs-OOH by lipoxygenases (LOXs), leading to ferroptosis. GPX4 roles as a protector to transfer PE-PUFAs-OOH to PE-OH. CoQ10, coenzyme Q10; DMT1, divalent metal transporter 1; FPN, ferroportin; Gln, glutamine; HAMP, hepcidin antimicrobial peptide; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; IREB2, iron-responsive element binding protein 2; NCOA4, Nuclear receptor coactivator 4; STEAP3: six-transmembrane epithelial antigen of the prostate 3.

Figure 2

Ferroptosis modulation in tumor. Small molecules such as erastin, sorafenib, glutamate, and sulfasalazine induce ferroptosis by inhibiting system Xc- and impeding cysteine uptake, which could result in a subsequent decline of glutathione and a decrease of cells’ anti-oxidative ability. mucin 1 C-terminal (MUC1-C) binds with CD44v to promote stability of the system Xc⁻. The cysteine level can also be supplemented by cellular methionine via the sulphur-transfer pathways. GPX4 can prevent ferroptosis by suppressing cellular lipid peroxides and the mevalonate (MVA) pathway is crucial for its maturation and the products of it (IPP and CoQ10) can promote synthesis of GPX4. Treatment FIN56 modulates squalene synthase (SQS) to reduce CoQ10. Ferroptosis inducer RSL3 can suppress GPX4 directly to regulate ferroptosis. The p62-Keap1-Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is able to regulate Nrf2-targeted genes such as heme oxygenase-1 (HO-1), ferritin heavy chain 1 (FTH1), and NAD(P)H: quinone oxidoreductase 1 (NQO1) against ferroptosis. CISD1, PHKG2, and IREB2 are important in regulating iron metabolism and ferroptosis. Ironchelators can inhibit ferroptosis. The HSPB1 also impedes ferroptosis by inhibiting increase of intracellular iron. In addition, p53 also regulate ferroptosis through inhibiting SLC7A11 and promoting lipid peroxides production. BSO, buthionine sulfoximine; FTH1, ferritin heavy chain 1; HSP, heat-shock protein; HO-1, heme oxygenase-1; MUC1-C, mucin 1 C-terminal; MVA, mevalonate; NQO1, NAD(P)H: quinone oxidoreductase 1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; SQS, squalene synthase.

Figure 3

Role of ferroptosis in cancer. AA, arachidonic acid; AdA, adrenaline; ACSL4, acyl-CoA synthetase long-chain family 4; cDC1, type 1 dendritic cell; CAF, cancer-associated fibroblast; DMT1, divalent metal transporter 1; DAMP, damage-associated molecular pattern; HETE, hydroxyeicosatetraenoic acid; HMGB1, high mobility group box 1; FPN, ferroportin; LF, lactoferrin; LIP, labile iron pool; LCN, lipocalin; LPCAT3, lysophosphatidylcholine acyltransferase 3; NTBI, non-transferrin-bound iron; NCOA4, nuclear receptor coactivator 4; NK cell, natural killer cell; PE, phosphatidylethanolamine; PTGS2, prostaglandin-endoperoxide synthase 2; SCARA5, scavenger receptor A member 5; TF, transferrin; TFR1, transferrin receptor 1; TAM, tumor-associated macrophage; TME, tumor microenvironment.