Mitochondria are the centers of intracellular iron metabolism. The endosome-mitochondria “kiss and run” interaction is a significant pathway widely studied to transport iron into mitochondria
[55][56][89,90]. Iron enters into the mitochondrial matrix through the outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM). Iron is stored in FtMt in the mitochondrial stroma or used to synthesize heme and Fe-S clusters. These two iron-containing factors are likely associated with ferroptosis
[29][51]. The mechanism by which iron is transported through OMM is still unknown, while transport on the IMM requires the assistance of the membrane transporter mitoferrin 1 (Mfrn1) and its homolog mitoferrin 2 (Mfrn2)
[57][91]. Friedreich’s ataxia (FRDA) is caused by a decrease in mitochondrial proteins frataxin (FXN), and one of the features is an iron overload on the mitochondria
[58][92].
4.2. The Role of Mitochondria in Inhibiting Ferroptosis
There are three main types of cellular protective systems against ferroptosis. Each of these three protective systems has its own unique subcellular localization. GPX4 is localized to the cytoplasm and mitochondria, FSP1 is localized to the plasma membrane, and DHODH is localized to the mitochondria. Among them, the inhibition of ferroptosis by mitochondria is mainly through GPX4 and DHODH
[59][96]. GPX4, a member of the glutathione peroxidase family, plays an important role in inhibiting ferroptosis. GPX4 is an inhibitor of lipid peroxidation, which can degrade small molecular peroxides and relatively complex lipid peroxides, and has shown inhibitory ability in adriamycin-induced lipid peroxidation
[60][97].
5. Ferroptosis Inducer
5.1. Ferroptosis Inducers Targeting Different Mechanisms
5.1.1. Ferroptosis Inducers Targeting the Production of ROS via Iron Accumulation
Iron accumulation in mitochondria produces mitochondrial ROS via the Fenton reaction, which uses ferrous ions as catalysts to convert H
2O
2 in cells into ROS to induce ferroptosis
[61][101]. DHA accelerates ferritin degradation and then promotes ROS accumulation in cells to induce ferroptosis by regulating the activity of the AMPK/mTOR/p70S6k signaling pathway
[62][102]. Auriculasin, isolated from Flemingia philippinensis, induces ferroptosis of colorectal cancer cells by increasing the accumulation of Fe
2+ which increases ROS production in cells
[63][103]. In conclusion, targeting the production of ROS via iron accumulation to induce ferroptosis may be an effective cancer therapy.
5.1.2. Ferroptosis Inducers Targeting System Xc−
System Xc
−, located in the cell membrane, mediates the transport of cysteine and glutamate. Glutamate is transferred to the outside of the cell, and simultaneously, cystine, which participates in the generation of GSH, is imported, thereby preventing the ferroptosis of cancer cells
[64][104]. Therefore, some molecules inhibiting system Xc
− via several targets have been indicated for treating cancers by inducing cancer cell ferroptosis. Erastin, specifically inhibiting the system, has been demonstrated to be effective in treating a variety of tumors, including meningioma, diffuse large B-cell lymphoma (DLBCL), and renal cell carcinoma
[14][65][66][29,105,106]. With the exact mechanism of ferroptosis induced by erastin, sulfasalazine, approved by the FDA, has been widely used in the treatment of endometrial cancer
[67][68][107,108].
5.1.3. Ferroptosis Inducers Targeting the Consumption of GSH
GSH is an essential member of the cellular antioxidative system, loss of which will break redox homeostasis and cause ROS accumulation, eventually triggering the ferroptosis of cancer cells
[69][111]. Artesunate, used as an anti-malarial drug previously, has been repurposed as an anticancer drug due to its induction of cell death in head and neck cancer via inducing ferroptosis by decreasing cellular GSH levels and increasing lipid ROS levels
[70][112]. To sum up, reducing the levels of GSH may be feasible to induce ferroptosis in tumor cells.
5.1.4. Ferroptosis Inducers Targeting GPX4
GPX4 converts L-OOH into non-toxic L-OH, preventing ferroptosis
[17][32]. ML-162 induces ferroptosis in thyroid cancer cells by reducing the activity of GPX4 (
Table 5 [71][113]. RSL3, a reagent containing electrophilic chloroacetamide, induces ferroptosis on DLBCL and renal cell carcinoma in vitro in a dose- and time-dependent manner through a decrease in the expression of GPX4
[14][29].
5.1.5. Ferroptosis Inducers Targeting DHODH
Dihydroorotate DHODH is reported to defend against ferroptosis, which operates dependent on mitochondrial GPX4 to inhibit ferroptosis in the IMM via reducing ubiquinone to ubiquinol, a radical-trapping antioxidant with anti-ferroptosis activity. In mitochondria, DHODH and GPX4 constitute two major ferroptosis defense systems by reducing the damage of LPO to mitochondria. Based on that, brequinar has been reported to damage the ferroptosis defense systems of low GPX4 tumors whose GPX4 defense system has low defense capability to inhibit their growth by inhibiting mitochondrial DHODH
[59][96].
5.1.6. Multiple Targeted Ferroptosis Inducers
Some molecules induce ferroptosis through the joint action of the multiple targets above, including GPX4, SLC7A11, system Xc
−, etc. Alloimperatorin induces breast cancer cell ferroptosis by reducing mRNA and protein expression levels of SLC7A11 and GPX4, which promotes the accumulation of Fe
2+, ROS, and MDA, thereby inhibiting cell growth and invasion
(Table 5) [72][114]. Bupivacaine, previously used as a local anesthetic, has recently been reported to modulate ferroptosis in bladder cancer by amplifying the level of Fe
2+ and restraining the expression of system Xc
− and GPX4
[73][115].
5.2. Ferroptosis-Based Combinational Cancer Therapy
Combining some of the above molecules will have a better therapeutic effect. Chemical hybridization of sulfasalazine and DHA promotes the death of brain tumor cells
[74][116]. Combined treatment with brequinar and sulfasalazine can induce ferroptosis, suppressing GPX4′s high tumor growth
[59][96].
5.3. Nanomedicines Treat Tumors via Inducing Ferroptosis
With better targetability in inducing ferroptosis by recombination with other substances, new nanoparticles have been developed to treat tumors. IpGdIO-Dox, a novel magnetic nanocatalyst set through iRGD-PEG-ss-PEG-modified gadolinium engineering magnetic iron oxide-loaded Dox, is reported for MRI-guided chemo- and ferroptosis synergistic cancer therapies. Specifically, ipGdIO-Dox induces cancer ferroptosis by releasing abundant Fe
2+ ions and then catalyzing H
2LPCA into highly toxic OH•, which damages mitochondria and cell membranes
[75][118].
6. Conclusions
In conclusion, as a form of regulatory cell death, ferroptosis mainly depends on iron-mediated oxidative damage and subsequent cell membrane damage. The key to inducing ferroptosis is to increase iron accumulation, free radical production, fatty acid supply, and lipid peroxidation. In recent years, ferroptosis has shown exciting prospects in tumor treatment. A large number of known drugs and molecules have been proven to be able to treat ferroptosis. The treatment strategies of ferroptosis have also begun to diversify, which brings hope for tumor treatment.