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From Mechanism to Medicine: Recent Advances in Ferroptosis from Top-Tier Publications

30 April 2025

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Ferroptosis is a distinct form of programmed cell death characterized by iron-dependent lipid peroxidation, first formally described by Dr.Brent Stockwell in 2012. Unlike apoptosis, necrosis, and autophagy, ferroptosis is driven by intracellular iron accumulation and lipid peroxides.

Key Mechanisms of Ferroptosis

1. Iron Metabolism Dysregulation Intracellular iron plays a pivotal role in ferroptosis by generating reactive oxygen species (ROS) via the Fenton reaction, initiating lipid peroxidation and cell death. Key steps include:
· Iron uptake and storage via transferrin receptor (TFR1) and ferritin.
· Iron release and utilization, with ferritin degradation elevating intracellular free iron.

2. Lipid Peroxidation Lipid peroxidation represents a hallmark characteristic of ferroptosis, primarily involving the oxidation of polyunsaturated fatty acids (PUFAs):
· Regulation of Lipid Peroxidation: PUFAs undergo esterification to phosphatidylethanolamines (PEs) through the enzymatic activity of acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), followed by oxidation to lipid peroxides via lipoxygenases.
· Lipid Peroxide Elimination: Cells employ multiple pathways to eliminate lipid peroxides, notably the glutathione peroxidase 4 (GPX4)-dependent antioxidant system.

3. Amino Acid and Antioxidant Imbalance Ferroptosis exhibits a strong correlation with cellular glutathione (GSH) synthesis and metabolism:
· Cystine Transport: Cystine enters cells through the SLC7A11/SLC3A2 heterodimer (System Xc⁻) and is reduced to cysteine for GSH synthesis.
· GSH Cycling: GSH maintains cellular antioxidant capacity through glutathione-disulphide reductase (GSR), which utilizes NADPH-derived electrons to reduce oxidized glutathione (GSSG) to GSH.

4. System Xc⁻ Dysfunction
System Xc⁻, a crucial cystine/glutamate antiporter, plays a vital role in ferroptosis initiation when dysfunctional.
· Reduced Cystine Uptake: System Xc⁻ facilitates cellular cystine import. Its dysfunction leads to decreased cystine uptake, consequently reducing GSH synthesis.
· Enhanced Glutamate Efflux: System Xc⁻ dysfunction increases glutamate efflux. As an excitatory neurotransmitter, elevated extracellular glutamate may exacerbate cellular injury.

Principal Research Applications

1. Cancer Therapeutics Ferroptosis presents significant potential in cancer treatment. Studies demonstrate high sensitivity of various cancer cells to ferroptosis inducers, particularly in drug-resistant lung, colorectal, and hepatocellular carcinomas. Therapeutic strategies include modulating fatty acid metabolism and cellular signalling pathways to compromise cancer cell membrane stability and enhance ferroptosis sensitivity. CD8⁺ T cell-secreted interferon-γ activates ACSL4 in cancer cells, promoting lipid peroxidation and ferroptosis induction. These findings offer novel directions for cancer immunotherapy and precision medicine.

2. Neurodegenerative Diseases Ferroptosis plays a significant role in neurodegenerative conditions. Iron accumulation is observed in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). In Alzheimer's disease, elevated brain iron levels precede β-amyloid and Tau protein aggregation, correlating positively with disease progression and cognitive decline. Ferroptosis modulation may offer therapeutic potential for these challenging conditions.

3. Ischemia-Reperfusion Injury In acute liver failure (ALF) models, ferroptosis initiation correlates with significant increases in n-6 polyunsaturated fatty acid peroxides. Iron overload inhibitors, such as UAMC-3203 and VBIT-12, demonstrate efficacy in mitigating ferroptosis and improving hepatic injury.

4. Inflammation and Immunity The interplay between ferroptosis and inflammatory responses represents an active research area. Studies indicate ferroptosis modulates inflammatory signalling pathways, including cGAS-STING, influencing immune responses. Furthermore, ferroptotic cell death releases damage-associated molecular patterns (DAMPs), activating immune system responses.

5. Lipid Metabolism and Mitochondrial Function Lipid metabolism plays a crucial role in ferroptosis. It has been recently revealed that phospholipids containing two polyunsaturated fatty acid acyl tails (PL-PUFA2s) are critical in ferroptosis. These rare lipids regulate mitochondrial homeostasis and ferroptosis through free fatty acid modulation.

Recent Advances in Ferroptosis Research

Figure 1. Reference 1

As led by Dr. Chengqian Yin, researchers investigated S-palmitoylation's regulatory effects on glutathione peroxidase 4 (GPX4) and its role in ferroptosis. Research discovered that the enzyme GPX4 undergoes palmitoylation at the cysteine residue C66. This modification enhances GPX4's stability, thereby suppressing ferroptosis. Inhibiting this palmitoylation sensitizes tumour cells to ferroptosis, offering potential therapeutic avenues.

Figure 2. Reference 2

Dr. Ping Gao and colleagues at the Department of Urology, Peking University First Hospital, identified that VSTM2L, a mitochondrial protein, binds to VDAC1 and hexokinase 2 (HK2), preventing VDAC1 oligomerization. This interaction maintains mitochondrial integrity and suppresses ferroptosis in prostate cancer cells, suggesting VSTM2L as a potential therapeutic target.

Figure 3. Reference 3

In the study led by Dr. Xiang Huang, researchers employed a genome-wide CRISPR/Cas9 combination with a TETon-Bifc reporter system to systematically identify METTL3/METTL14 heterodimer dissociating regulators in A549 cells. Additionally, they conducted CUT&Tag sequencing on both wild-type METTL3 and METTL3-3KR mutant A549 cells using the GeneMind SURFSeq 5000 high-throughput platform. These analyses demonstrated that METTL3 acetylation impairs its recruitment to H3k27ac-marked chromatin, providing genomic-level evidence for the regulatory role of acetylation in modulating MTC chromatin association.

Figure 4. Reference 4

Dr. Ana García Sáez, Dr. Bernhard Röck and the team from University of Cologne demonstrated that ferroptosis can propagate to adjacent cells through direct plasma membrane contacts. Using an optogenetic tool, Opto-GPX4Deg, they showed that lipid peroxidation spreads in a contact- and iron-dependent manner, highlighting a novel mechanism of cell death propagation.

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Ferrostatin-1 (A228648): A ferroptosis inhibitor with an IC₅₀ of 60 nM, demonstrating neuroprotective and antitumor properties. Used for investigating ferroptosis in neurodegenerative diseases and cancer.

Liproxstatin-1 (A120662): A selective lipid peroxidase inhibitor with high affinity (IC₅₀: 22 nM). Shows antioxidant and anti-inflammatory properties, useful for lipid metabolism and oxidative stress research.

Cisplatin (A210558): An antineoplastic agent that induces DNA damage through DNA crosslinking, activating ferroptosis and inducing autophagy.

SP600125 (A155219): Selectively inhibits JNK1, JNK2, and JNK3 (IC₅₀: 40 nM, 50 nM, and 90 nM respectively). Shows anti-inflammatory and antitumor properties and acts as a ferroptosis inhibitor.

Erastin (A145112): Induces ferroptosis by inhibiting VDAC2/VDAC3, causing ROS accumulation. Disrupts mPTP and shows antitumor activity. Note: Solution unstable; prepare fresh.

RSL3 (A108537): Inhibits GPX4, inducing ferroptosis in head and neck cancer cells. Increases p62 and Nrf2 protein levels in HN3-resistant cells, inactivating Keap1.

Sorafenib (A316727): A multi-target kinase inhibitor affecting Raf-1, B-RAF, and receptor tyrosine kinases VEGFR2, VEGFR3, PDGFRβ, FLT3, and c-Kit with varying IC₅₀ values.

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References

[1]Huang B, Wang H, Liu S, et al. Palmitoylation-dependent regulation of GPX4 suppresses ferroptosis.

[2]Yang J, Lu X, Hao JL, et al. VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis.

[3]Huang X, Zhang J, Li Y, et al. Spatial control of m6A deposition on enhancer and promoter RNAs through co-acetylation of METTL3 and H3K27 on chromatin.

[4]Roeck BF, Lotfipour Nasudivar S, Vorndran MRH, et al. Ferroptosis spreads to neighboring cells via plasma membrane contacts.

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