Written by Dr. Sanjana V.B Bhms,dbrm,cdn

Founder & medical director of siahmsr wellness.in

All rights reserved with siahmsr digital healthcare[siahmsr wellness]

Reviewed by SIAHMSR medical team.

Ferroptosis 

      It is a mode of regulated cell death caused by unbalanced lipid redox metabolism. It happens in various tissue injuries, cancers, nervous system diseases, ischemia reperfusion injury, kidney injury and blood diseases. Certain neurodegenerative disorders are also linked with ferroptosis.

   The occurrence of ferroptosis is iron dependent. However, the exact molecular mechanism is not clear. Glutathione peroxidase is a great suppressor of ferroptosis. Vitamin E is yet another important antioxidant preventing lipid peroxidation and ferroptosis. Activating or blocking of ferroptosis pathway is  constantly researched by medical research wings for preventing various diseases. Ferroptosis is actively different from apoptosis, necrosis and autophagy in cell morphology and function.

Malignancies associated ferroptosis  include :

·       Pancreatic cancer

·       Hepatocellular carcinoma.

·       Gastric cancer

·       Colorectal cancer

·       Breast cancer

·       Lung cancer

·       Adrenocortical carcinomas

·       Ovarian cancer

·       Melanoma

 Significance 

   Extensive research studies suggest that ferroptosis plays a pivotal role in tumor suppression, thus it opens up a new  avenue for extensive research and  cancer therapy.

Drug resistance is a major challenge in cancer therapy. Ferroptosis  has been correlated with cancer therapy resistance, and inducing ferroptosis has shown to reverse drug resistance to cancer.

In 2014 a study reported that renal cell carcinoma is particularly susceptible to ferroptosis and identified glutathione peroxidase 4 (GPX4) as a central regulator of ferroptosis.

According to Yang et al.’s study ferroptosis  is induced with different ferroptosis-inducing compounds (FINs) and found that all FINs inhibited  glutathione peroxidase 4 [GPX4 ]directly or indirectly through intracellular glutathione [ GSH ]depletion. They thus concluded that GPX4 is the key regulator of ferroptosis.

 Ferroptosis  has been explained to happen through the following pathways: 

canonical GPX4-regulated pathway, iron metabolism pathway and lipid metabolism pathway.

Canonical GPX4-regulated pathway

In human body  glutathione peroxidase 4 [GPX4 ]appears to play a key role in catalyzing the reduction of phospholipid hydroperoxides (PLOOH) into corresponding phospholipid alcohols .

GSH or glutathione is necessary for the normal physiological function of GPX4.

Inactivation  of GPX4 can lead to the accumulation of PLOOH, thus inducing cell membrane damage and ferroptotic death.

Iron metabolism pathway

Ferroptosis  is  an iron-dependent form of cell death, characterized by an increase in the small pool of Fe2+.  Cellular  iron uptake was mostly mediated by the binding of serum transferrin to the transferrin receptor and transferrin endocytosis .

 In 2016 a study demonstrated that autophagy contributes to ferroptosis by degrading ferritin in fibroblasts and cancer cells.

Lipid metabolism pathway

The specific feature of ferroptosis is increased lipid peroxidation; thus, the metabolism of lipid peroxides is considered to be critical in the process of ferroptosis.

Ferroptosis is likely performed by the peroxidation of membrane phospholipids to produce PLOOH and the decomposition of PLOOH to generate 4-hydroxynonenal or malondialdehyde. The products of lipid peroxidation cause membrane instability and permeabilization and eventually lead to cell death.

As per the mechanisms governing ferroptosis, there are three main pathways to reverse chemotherapy resistance in cancer that include  the canonical GPX4-regulated pathway, iron metabolism pathway, and lipid metabolism pathway.

Pharmacological or genetic regulation of ferroptosis  can overcome chemotherapy drug resistance in cancer patients .This information about ferroptosis is therefore a significant milestone in cancer therapy.

    REFERENCES – For further reading

1.    https://pubmed.ncbi.nlm.nih.gov/34267193/

2.    https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01530-y#:~:text=Ferroptosis%20is%20an%20intracellular%20iron,new%20opportunities%20for%20cancer%20therapy.

3.    https://pubmed.ncbi.nlm.nih.gov/17568748/

4.    https://www.nature.com/articles/s41419-020-2298-2