Ferroptosis: A New Road towards Cancer Management

Abstract

Ferroptosis is a recently described programmed cell death mechanism that is characterized by the buildup of iron (Fe)-dependent lipid peroxides in cells and is morphologically, biochemically, and genetically distinct from other forms of cell death, having emerged to play an important role in cancer biology. Ferroptosis has significant importance during cancer treatment because of the combination of factors, including suppression of the glutathione peroxidase 4 (Gpx4), cysteine deficiency, and arachidonoyl (AA) peroxidation, which cause cells to undergo ferroptosis. However, the physiological significance of ferroptosis throughout development is still not fully understood. This current review is focused on the factors and molecular mechanisms with the diagrammatic illustrations of ferroptosis that have a role in the initiation and sensitivity of ferroptosis in various malignancies. This knowledge will open a new road for research in oncology and cancer management.

Keywords: cancer; ferroptosis; iron; molecular mechanisms; tumor.

Figure 1

The ferroptosis signaling pathway. Ferroptosis is regulated by two major regulatory mechanisms, namely the cystine/glutathione (GSH)/glutathione peroxidase 4 (Gpx4) axis and the NAD(P)H/ferroptosis suppressor protein 1 (FSP1)/ubiquinone (CoQ10) axis. The cystine/glutathione (GSH)/glutathione peroxidase 4 (Gpx4) axis regulates ferroptosis suppression through the cystine/GSH/Gpx4 nexus is accomplished by the main stages of cystine absorption and decrease, respectively, GSH production, and Gpx4 activation, among others, and the conversion of oxidized phospholipids (PLs) into their homologous alcohols (PL-OH) by the enzyme Gpx4, which uses GSH as a substrate. It has been shown that the enzymes acyl-CoA synthetase long-chain family member 4 (ACSL4) as well as lysophosphatidylcholine acyltransferase 3 (LPCAT3) are involved in integrating polyunsaturated fatty acids (PUFAs) within cellular membranes, making them susceptible to ferroptosis activation. As a result, the oxidation of lipid bilayers may proceed enzymatically and/or nonenzymatically by auto-oxidation, depending on the situation. The antiferroptotic activity of FSP1 in the NAD(P)H/FSP1/CoQ10 system is attributed to its oxidoreductase activity, which is activated by converting extramitochondrial CoQ10 to ubiquinol using NAD(P)H/H+. To avoid lipid peroxidation, ubiquinol either reduces lipid radicals (PL-OO) directly or indirectly via the use of vitamin E (-tocopherol) must be present. Apart from that, the mevalonate pathway produces precursors for CoQ10 and squalene, the latter of which is beneficial in the prevention of ferroptosis because of its antioxidant action.

Figure 2

The involvement of ferroptosis in the development of cancer. First and foremost, p53 can control ferroptosis both favorably and negatively. On the one hand, p53 may promote ferroptosis by decreasing the expression of SLC7A11 while simultaneously inhibiting the regulation of SAT1, GLS2, and PTGS2. On the other hand, p53 can inhibit ferroptosis by enhanced expression of SAT1, GLS2, as well as PTGS2. On the other side, p53 can reduce ferroptosis by inhibiting DPP4 action and increasing the production of the protein p21. Second, small nucleolar RNA (snRNA) is a new regulator of ferroptosis control, and this includes long noncoding RNA (lncRNA), microRNA, and circRNA. Differential mechanisms that regulate ferroptosis may be classified into three types: some suggest that LINC00336 and circ-TTBK2 might act as competitor endogenous RNAs (ceRNAs), binding to miRNAs and regulating miRNA production, hence altering the ferroptosis process. The microRNAs MiR-214 and MiR-137 may influence the formation of genes implicated in ferroptosis. lncRNAs p53RRA enhance ferroptosis through interacting with ferroptosis-related proteins, according to research. Third, under conditions of OS, autophagy-dependent ferroptosis (ADF) promotes pro-tumorigenic M2 macrophage polarization and the production of tumor-associated macrophages (TAMs), both of which are necessary for cancer development.

Figure 3

The promising use of ferroptosis for cancer treatment. A representation of ferroptosis-based cancer therapeutics, which includes small chemicals, nanoparticles, exosomes, and gene technology. It is possible to use nanomaterials as drug-inducing ferroptosis and Fe carriers in the chemotherapy combined with hyperthermia and autophagy, etc. Because exosomes are more biocompatible and less immunogenic than nanomaterials, they have a better chance of being used in clinical trials. One of the most difficult aspects of gene technology is that it may be broken down into two categories: “knockdown” and “transfection”. It will be confronted with a variety of difficulties.