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The programmed cell death mechanism known as ferroptosis occurs through lipid peroxidation processes that require iron. The scientific team led by Brent R. Stockwell presented the ferroptosis concept to the scientific community in 2012. Ferroptosis is a programmed cell death process that requires iron and stands apart from apoptosis through its unique combination of lipid peroxide accumulation and excess iron ions. The emergence and progression of multiple diseases such as neurodegenerative conditions, cancer, and cardiovascular diseases heavily depend on this particular form of cell death.
Figure 1. Ferroptosis regulators associated with iron metabolism. (Sources: Du Y, et al. 2022)
Ferroptosis operates through several hierarchical mechanisms which mainly encompass the following elements:
1. Iron metabolism and lipid peroxidation:
Iron ions trigger the creation of reactive oxygen species that start lipid peroxidation which damages phospholipids within cellular membranes through oxidative stress.
The combined depletion of glutathione (GSH) and GPX4 inactivation forms vital links in ferroptosis progression. GPX4 functions as a lipid peroxide removal enzyme which leads to lipid peroxide accumulation when it loses activity.
2. Signaling pathways and regulatory networks:
Multiple signaling pathways including epigenetic mechanisms and various transcriptional and translational regulations control ferroptosis.
Antioxidant systems form the core defense mechanisms which encompass GPX4, FSP1/ubiquinol, and the DHBP system. These systems preserve cellular balance by removing lipid peroxides.
3. Accumulation and metabolism of iron ions:
Transferrin transports iron ions into cells where divalent metal transporter 1 (DMT1) converts them to Fe2+ and these ions accumulate in cellular iron stores or bind to ferritin.
The excessive amount of iron ions accelerates lipid peroxidation which results in cell membrane damage and subsequent loss of cell function.
4. Morphological characteristics:
Ferroptotic cells display specific morphological traits such as reduced mitochondrial volume and membrane density while exhibiting ruptured mitochondrial outer membranes and diminished or absent cristae. The structure of the cell nucleus remains intact because the chromatin remains uncondensed and apoptotic bodies do not develop.
Multiple diseases such as Alzheimer's disease as well as cancer and cardiovascular disease depend on ferroptosis during both development and progression stages. Medications used in chemotherapy target cancer treatment through ferroptosis induction thereby eliminating cancer cells while ferroptosis itself serves as a potential therapeutic target.
Here is a compilation of small molecule drugs known to trigger ferroptosis.
| Drug Name | Target | Molecular Pathway | Mechanism of Action | Application Case |
| Eristan | System Xc- (Cystine/glutamate antiporter) | Inhibition of System Xc- → ↓ GSH → GPX4 activation → lipid peroxidation → ferroptosis | Inhibits System Xc- activity, reduces GSH levels | Anti-cancer effects in gastric and lung cancers |
| SAS | System Xc- | Similar to Eristan (indirect ferroptosis via GSH synthesis inhibition) | Inhibits cystine transporter, reduces GSH synthesis and directly inhibits GPX4 | Potential therapeutic effects in liver fibrosis and non-alcoholic fatty liver disease |
| Sorafenib | Multi-kinase inhibitor | System Xc- inhibition → GSH depletion + ER stress → ferroptosis | Inhibits System Xc- mediated cystine uptake | Anti-cancer effects in liver and kidney cancers (with high toxicity to normal cells) |
| RSL3 | GPX4 | Direct GPX4 inhibition → lipid peroxidation → ferroptosis | Binds to GPX4 active site | Significant anti-cancer effects in gastric and lung cancers |
| ML162 | GPX4 | Same as RSL3 | Direct GPX4 inhibition | Anti-cancer effects in multiple cancers |
| FIN56 | GPX4 | GPX4 degradation via squalene synthase (SQS) activation | Binds and activates SQS, induces GPX4 degradation | Anti-cancer effects in gastric and lung cancers |
| CL56 | GPX4 | Same as RSL3 | Direct GPX4 inhibition | Anti-cancer effects in multiple cancers |
| Turofexin | GPX4/System Xc- (unclear) | May affect lipid peroxidation or GSH synthesis | Possible GPX4 inhibition | Anti-cancer effects in multiple cancers (mechanism under study) |
| Hemin | Free iron ions | ↑ Free iron → lipid peroxidation → ferroptosis | Increases intracellular free iron | Anti-cancer effects in gastric and lung cancers |
| NDP4928 | FSP1/CoQ pathway | ↑ FSP1/CoQ activity → ↑ GSH → enhanced ferroptosis | Enhances FSP1/CoQ pathway | Anti-cancer effects in multiple cancers |
| DPI7 | GPX4 | Same as RSL3 | Direct GPX4 inhibition | Anti-cancer effects in multiple cancers |
| EF24 | GPX4/System Xc- (unclear) | May affect lipid peroxidation or GSH synthesis | Possible GPX4 inhibition | Anti-cancer effects in multiple cancers |
| IKE | System Xc- | Similar to Eristan (indirect ferroptosis via GSH synthesis inhibition) | System Xc- inhibition | Anti-cancer effects in gastric and lung cancers |
| SASP | System Xc- | Similar to Eristan and SAS | System Xc- inhibition | Potential therapeutic effects in liver fibrosis |
| BSO | GSH synthesis pathway | ↓ GSH synthesis → GPX4 activation → lipid peroxidation → ferroptosis | Inhibits γ-glutamylcysteine synthetase (GSH synthesis rate-limiting enzyme) | Anti-cancer effects in gastric and lung cancers |
Various small molecule drugs trigger ferroptosis through multiple mechanisms such as GSH synthesis inhibition, GPX4 activity inhibition, increased intracellular iron levels, and lipid metabolism disruption. The studies establish essential theoretical and experimental foundations for utilizing ferroptosis as a cancer treatment strategy.
Existing data reveals that research advances for ferroptosis-inducing drugs in tumor treatment focus mainly on the subsequent areas.
1. Ferroptosis mechanism and tumor treatment potential:
Iron-dependent ferroptosis functions as a distinct type of cellular death that stands apart from conventional apoptosis and necrosis. Cell death occurs through the accumulation of iron ions and the production of lipid peroxides during the process. Multiple tumor types which develop resistance to standard therapies such as non-small cell lung cancer and breast cancer utilize ferroptosis as their primary mechanism.
Researchers have found that combining ferroptosis inducers with conventional cancer treatments improves both therapy effectiveness and tumor management outcomes.
2. Ferroptosis inducers can be organized into three main groups based on their mechanisms of action.
Ferroptosis inducers are mainly divided into three categories: Three drug categories induce ferroptosis including Xc system inhibitors like sorafenib and alastine, glutathione synthesis inhibitors such as sulfasalazine and GPX4 inhibitors including ethacrynic acid.
Various mechanisms trigger ferroptosis when drugs operate to consume glutathione and inhibit GPX4 directly or indirectly while inducing the Fenton reaction.
3. Combination of nanotechnology and ferroptosis inducers:
Nanomaterials provide important benefits for enhancing solubility, stability and targeting capabilities of ferroptosis inducers. Iron ion-based nanomedicines that coordinate with single nucleic acids can trigger ferroptosis in human malignant glioma U87L cells.
Nanoparticles enhance therapeutic effectiveness by targeting cancer cells while simultaneously reducing normal tissue toxicity.
The FDA currently permits treatment with certain ferroptosis inducers including sorafenib alongside alastine and sulfafarazine for cancer therapy. Multiple studies both preclinical and clinical demonstrate that ferroptosis inducers show significant promise for defeating drug resistance and boosting treatment effectiveness. The combination of ursolic acid with sorafenib triggers ferroptosis in liver cancer cells by activating the Nrf2/HO-1/GPX4 signaling pathway.
Subsequent investigations should explore ferroptosis inducers' specific molecular targets while combining them with emerging treatment techniques such as immunotherapy and photodynamic therapy to improve treatment accuracy and efficacy.
Extensive studies need to confirm ferroptosis inducers' effectiveness against difficult-to-treat cancers including colorectal and pancreatic cancer.
Ferroptosis-inducing drugs have shown strong potential in cancer therapy as they enable traditional treatments to work better while defeating drug resistance. Current clinical applications of ferroptosis inducers exist at a preliminary stage which demands further research and development to achieve widespread clinical application.
The clinical transformation of ferroptosis inducers faces significant challenges due to their low bioavailability and poor water solubility combined with inadequate targeting capabilities.
The toxicity of ferroptosis inducers toward normal cells including DNA damage in bone marrow cells requires careful monitoring during clinical use.
The absence of effective biomarkers for ferroptosis during live treatment conditions limits the clinical use of ferroptosis-inducing drugs.
While ferroptosis inducers show promise in cancer therapy their clinical testing remains at a preliminary phase and presents numerous obstacles. Future studies must delve deeper into understanding the mechanism of action while enhancing drug design and clinical application safety and effectiveness.
Programmed cell death through ferroptosis occurs when lipid peroxidation depends on iron. The research team led by Brent R. Stockwell proposed this distinct cell death method in 2012 which stands apart from apoptosis, necrosis, and autophagy through its unique morphological and molecular features including lipid peroxide build-up and iron ion accumulation.
The primary barriers involve low bioavailability combined with inadequate water solubility and insufficient targeting capability. These drugs could harm healthy cells because scientists have not yet developed reliable biomarkers to detect ferroptosis in living organisms which restricts their broad clinical application.
References
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