Ferroptosis Inducers: Current Research and Therapeutic Outlook

Cell death is essential for maintaining health and combating disease. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has gained attention for its potential in treating cancer, neurodegeneration, and other conditions. Unlike apoptosis or necrosis, ferroptosis operates through distinct biochemical mechanisms, making it an attractive therapeutic target.

Researchers are exploring compounds that induce ferroptosis to selectively eliminate malignant or dysfunctional cells. Understanding these inducers could lead to novel treatments where conventional therapies fall short.

Key Molecular Pathways

Ferroptosis is regulated by molecular pathways that control lipid peroxidation, iron metabolism, and antioxidant defenses. Central to this process is glutathione peroxidase 4 (GPX4), which neutralizes lipid hydroperoxides and prevents oxidative membrane damage. When GPX4 activity is inhibited or glutathione (GSH) is depleted, lipid peroxidation becomes uncontrolled, leading to membrane rupture and cell death. This reliance on GPX4 distinguishes ferroptosis from apoptosis, which depends on caspase activation.

Polyunsaturated fatty acids (PUFAs) in phospholipids serve as substrates for lipid peroxidation, driven by both enzymatic and non-enzymatic processes. Lipoxygenases (LOXs) catalyze PUFA oxidation, while the Fenton reaction—where ferrous iron (Fe²⁺) reacts with hydrogen peroxide to generate hydroxyl radicals—amplifies oxidative stress, accelerating lipid peroxidation. This dependence on iron makes ferroptosis uniquely sensitive to iron availability.

Several regulatory nodes influence ferroptosis susceptibility. The system Xc⁻ antiporter, composed of SLC7A11 and SLC3A2, imports cystine for GSH synthesis. Inhibiting system Xc⁻ depletes GSH, impairing GPX4 and sensitizing cells to ferroptosis. The mevalonate pathway, which produces coenzyme Q10 (CoQ10), and the ferroptosis suppressor protein 1 (FSP1) pathway provide alternative antioxidant defenses. Disrupting these mechanisms enhances ferroptotic cell death, offering therapeutic strategies for diseases where ferroptosis induction is beneficial.

Iron-Dependent Induction

Iron is not just a cofactor in ferroptosis; it actively drives the process by facilitating lipid peroxidation through Fenton chemistry and enzymatic oxidation. Intracellular iron homeostasis is regulated by proteins like transferrin, ferritin, and ferroportin, which control iron uptake, storage, and export. Disruptions in this system can push cells toward ferroptosis, particularly when excess Fe²⁺ accumulates in the labile iron pool (LIP), a reservoir of bioavailable iron. Fe²⁺ fuels the Fenton reaction, generating hydroxyl radicals that initiate oxidative damage to lipid membranes.

Iron regulatory proteins (IRPs) modulate transferrin receptor 1 (TFR1) and ferritin expression to maintain iron balance. Under iron depletion, IRPs increase TFR1 expression to boost iron import while suppressing ferritin synthesis to minimize storage. Conversely, excessive iron uptake or ferritin degradation via ferritinophagy—a selective autophagic process—elevates intracellular Fe²⁺ levels, sensitizing cells to ferroptosis. Nuclear receptor coactivator 4 (NCOA4) promotes ferritin degradation, enhancing susceptibility to lipid peroxidation.

Exogenous iron sources also influence ferroptosis sensitivity. Iron supplementation through ferric ammonium citrate or iron dextran exacerbates ferroptosis in cancer cells, suggesting a therapeutic avenue for iron-based ferroptosis induction. Conversely, iron chelators like deferoxamine (DFO) and ciclopirox inhibit ferroptosis by reducing Fe²⁺ availability. These findings highlight the role of iron bioavailability in ferroptotic outcomes and provide a rationale for targeting iron metabolism in ferroptosis-related therapies.

Major Classes Of Synthetic Inducers

Synthetic ferroptosis inducers manipulate lipid peroxidation and disrupt antioxidant defenses. These compounds typically inhibit protective enzymes, alter lipid metabolism, or increase oxidative stress to drive ferroptotic death. The most studied synthetic inducers include GPX4 inhibitors, system Xc⁻ blockers, and iron-based catalysts.

GPX4 inhibitors are among the most potent ferroptosis inducers. RSL3 covalently binds the selenocysteine residue in GPX4, inactivating the enzyme and preventing lipid hydroperoxide detoxification. ML162 and ML210 achieve similar effects through irreversible GPX4 inhibition, demonstrating high potency in various cancer cell lines. These inhibitors have shown promise in preclinical cancer models, particularly in drug-resistant tumors.

System Xc⁻ inhibitors, such as erastin and sulfasalazine, limit cystine import, depleting intracellular GSH and indirectly impairing GPX4. Erastin selectively targets the SLC7A11 subunit of system Xc⁻, reducing cystine availability and amplifying oxidative stress. Sulfasalazine, an FDA-approved drug for inflammatory conditions, has been repurposed in ferroptosis research, showing potential for combination cancer therapies.

Iron-based catalysts leverage iron’s role in lipid peroxidation. FIN56 accelerates GPX4 degradation while depleting CoQ10, a lipid antioxidant. FINO2 generates reactive oxygen species through iron-dependent mechanisms, amplifying oxidative damage. These compounds demonstrate how targeting multiple pathways can enhance ferroptosis induction for therapeutic applications.

Naturally Sourced Inducers

Natural compounds from plants, fungi, and microorganisms offer diverse mechanisms to drive lipid peroxidation and oxidative stress. Many exhibit pro-oxidant properties by disrupting antioxidant defenses or facilitating iron-dependent oxidation, making them valuable therapeutic candidates.

Curcumin, a polyphenol from Curcuma longa, induces ferroptosis by depleting GSH and increasing intracellular iron levels. It downregulates SLC7A11, impairing cystine uptake and indirectly inhibiting GPX4. Baicalein, a flavone from Scutellaria baicalensis, directly inhibits lipoxygenases, exacerbating lipid peroxidation. These natural compounds have shown selective oxidative stress induction in malignant cells, presenting a potential therapeutic advantage.

Berberine, an isoquinoline alkaloid from Berberis species, enhances ferroptosis by disrupting mitochondrial function and promoting reactive oxygen species (ROS) accumulation. Its effects are pronounced in hepatocellular carcinoma models, where it sensitizes tumor cells to ferroptotic death. Artemisinin, a sesquiterpene lactone from Artemisia annua, induces iron-dependent cytotoxicity through free radical generation. Its derivative, dihydroartemisinin, amplifies lipid peroxidation through iron-mediated activation.

Cross-Talk With Other Cell Death Pathways

Ferroptosis intersects with multiple regulated cell death pathways, influencing cellular fate. This interplay is evident in its overlap with apoptosis, where oxidative stress serves as a common trigger. While apoptosis relies on caspase activation and mitochondrial outer membrane permeabilization, ferroptosis progresses independently, driven by lipid peroxidation and iron accumulation. However, apoptotic regulators like p53 can modulate ferroptosis susceptibility by repressing SLC7A11, limiting cystine uptake, and weakening antioxidant defenses.

Necroptosis, a caspase-independent form of programmed necrosis, also shares mechanistic links with ferroptosis through reactive oxygen species involvement. The necroptotic kinases RIPK1 and RIPK3 regulate oxidative stress, contributing to lipid peroxidation. Conversely, GPX4 inhibition can enhance necroptotic signaling, suggesting bidirectional regulation.

Autophagy further complicates this network, as ferritin degradation via ferritinophagy increases intracellular iron levels, sensitizing cells to ferroptosis. Autophagy-related proteins such as Beclin-1 and ATG5 regulate ferroptosis, promoting or suppressing cell death depending on cellular context. Understanding this cross-talk could inform therapeutic strategies that target multiple pathways to enhance treatment efficacy.