Science Note: Ferroptosis

Ferroptosis Activation, Inhibition, and Sensitization

Ferroptosis is a form of programmed cell death characterized by the accumulation of lipid peroxides to lethal levels and is distinct from other forms of cell death such as apoptosis or necrosis. In cancer, ferroptosis can act as a double-edged sword: on the one hand, inducing ferroptosis in cancer cells may be a promising therapeutic strategy, as many cancers are resistant to traditional forms of cell death such as apoptosis. On the other hand, cancer cells can develop resistance to ferroptosis, which contributes to therapy resistance and tumor progression. Understanding and manipulating the pathways that regulate ferroptosis in cancer cells holds the potential for developing novel cancer treatments and overcoming resistance to existing therapies.

Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance
Click here for the original article: Hao Zheng, et. al., Nature Cancer, 2024.

7-Dehydrocholesterol is an endogenous suppressor of ferroptosis
Click here for the original article: Florencio Porto Freitas et. al., Nature, 2024.

Sensitization of cancer cells to ferroptosis coincident with cell cycle arrest
Click here for the original article: Jason Rodencal et. al., Cell Chemical Biology, 2023.

Point of Interest
- Chemoresistant cancer-derived organoids exhibited increased expression of LGR4 and activation of the Wnt signaling pathway.

- Inhibition of LGR4-Wnt signaling sensitized drug-induced ferroptosis.

- LGR4-dependent Wnt signaling upregulated SLC7A11, a key inhibitor of ferroptosis, leading to drug resistance.

Point of Interest
- High concentrations of 7-DHC are cytotoxic to developing neurons by promoting lipid peroxidation.

- On the other hand, 7-DHC accumulation confers a prosurvival function in cancer cells.

- 7-DHC effectively protects (phospho)lipids from autoxidation and subsequent fragmentation due to its superior reactivity with peroxyl radicals.

- Accumulation of 7-DHC induces a shift to a ferroptosis-resistant state in tumors.

Point of Interest
- Stabilization of p53 and inhibition of CDK4/6 enhance ferroptosis induced by GPX4 inhibitors.

- Stabilization of p53 and inhibition of CDK4/6 decrease the expression of MBOAT1 and EMP2.

- Loss of EMP2 increases cell sensitivity to GPX4 inhibitors by altering lipid metabolism.

- An orally bioavailable GPX4 inhibitor shows in vivo activity.
Related Applications

The simultaneous detection of lysosomal function with Mitochondrial ROS and intracellular Fe2+

Lysosomal Function and Iron Homeostasis

 

 

Recent reports suggest that lysosomal neutralization can result in iron depletion, consequently leading to the disruption of cell viability. To verify this, HeLa cells were labeled with FerroOrange for Fe2+ detection, and the lysosomal mass and pH were separately detected with LysoPrime DeepRed and pHLys Green (a product currently under development). Co-staining with FerroOrange and Lysosomal dyes demonstrated that Bafilomycin A1 (Baf. A1), an inhibitor of lysosomal acidification, causes iron depletion consistent with the findings reported in the article. Interestingly, the iron chelator, Deferiprone (DFP), did not impact lysosomal pH, suggesting that lysosomal function plays a key role in managing iron homeostasis.

Reference: Ross A Weber, et. al., Mol Cell (2020)

Products in Use
   - FerroOrange
   - pHLys Green*
   - LysoPrime Deep Red

*pHLys Green is available as the "Lysosomal Acidic pH Detection Kit-Green/Deep Red". 
Related Techniques
           Intracellular lipid peroxidation measurement Liperfluo
           Mitochondria lipid peroxidation measurement MitoPeDPP
           Intracellular ferrous ion (Fe2+) detection FerroOrange
           Mitochondria ferrous ion (Fe2+) detection Mito-FerroGreen
           Mitochondrial superoxide detection MitoBright ROS Deep Red - Mitochondrial Superoxide Detection
           Total ROS detection Highly sensitive DCFH-DA or Photo-oxidation Resistant DCFH-DA 
           Lipid droplets detection Lipi-Blue / Green / Red / Deep Red
           Antibody/Protein labeling with fast and
           high recovery		 Fluorescein, Biotin, and Peroxidase Labeling Kit - NH2

What is Ferroptosis?

“Ferroptosis” was coined by Stockwell et al. at Columbia University in 2012 and described as a form of iron-dependent cell death. * It was reported to be a form of programmed cell death by the Nomenclature Committee on Cell Death (NCCD) in 2018.
Ferroptosis is a form of programmed cell death caused by iron ion-dependent accumulation of lipid peroxides. Ferroptosis has been shown to follow a different cell death pathway from apoptosis and thus is attracting attention as a new target for cancer therapy. It has also been found to be associated with various diseases, such as neurodegenerative diseases, cerebral apoplexy, and hepatitis (NASH).

*S. J. Dixon, B. R. Stockwell, et al., Ferroptosis: an iron-dependent form of nonapoptotic cell death., Cell, 2012, 149(5), 1060.

 

 

 

How Does Ferroptosis Cause Cell Death?

Ferroptosis is characterized by the accumulation of lipid peroxides. Lipid peroxides are formed from oxidation of polyunsaturated fatty acids (PUFA) in membrane phospholipids, with iron suggested to be involved. Intracellular glutathione peroxidase 4 (GPX4) uses reduced glutathione (GSH), an antioxidant, to reduce lipid peroxides generated by reactive oxygen species (ROS).*
However, when lipid peroxides accumulate due to GPX4 disruption or GSH depletion, ferroptosis is triggered.

*Stockwell et al, a leading researcher in the field of ferroptosis, summarized inhibitors, inducers, and detection indicators of ferroptosis in the following review, in which Dojindo’s Liperfluo is introduced for detection of lipid peroxides.

B. R. Stockwell, et al., "Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease.", Cell, 2017, 171, 273.

 

 

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