A team of researchers at Shandong University in China conducted a genetic and pharmacological study to assess the role of cholesterol metabolism in safeguarding cells against ferroptosis, with the findings being available in Nature.
Ferroptosis is a form of programmed cell death triggered by the accumulation of iron-dependent lipid peroxides on cell membranes.
The regulation of ferroptosis is associated with multiple signalling pathways, and mounting evidence indicates its involvement in regulating systemic disorders, including neurodegenerative diseases and organ damage.
Results indicated that ferroptosis can be induced through either extrinsic or intrinsic pathways, and that altering cholesterol levels can affect a cell’s susceptibility to ferroptosis.
It was also found that Fatty acid metabolism, an integral component of lipid metabolism, plays a significant role in ferroptosis, with the mevalonate pathway being responsible for endogenous cholesterol biosynthesis.
Cholesterol and certain sterol metabolites in the mevalonate pathway serve as regulators of cholesterol metabolism.
In this particular study, researchers hypothesised that cholesterol and its metabolites could influence cell sensitivity to ferroptosis.
A small-scale screening of commercially available sterol metabolites/derivatives as possible modulators of ferroptosis led the researcher to identify cholesterol and desmosterol as endogenous ferroptosis inhibitors.
Their findings revealed that these two metabolites in the mevalonate pathway exerted their anti-ferroptotic functions through the same mechanism: accelerating the degradation of Squalene Epoxidase (SQLE) to elevate intracellular levels of both Squalene and Coenzyme Q (CoQ).
Coenzyme Q and Squalene, two important lipid metabolites, have been identified as novel lipid peroxide scavengers, alongside the GPX4 protein. The findings suggest that boosting cellular concentrations of Squalene and CoQ can impede ferroptosis, emphasising the vital roles of both Squalene and CoQ as significant downstream factors for cholesterol and desmosterol in the regulation of ferroptosis.
“Understanding the intricate interplay between lipid metabolism and ferroptosis opens new avenues for nutritional strategies. The study’s discovery suggests the pivotal role of cholesterol and its metabolites in cellular health, offering insights into potential dietary interventions, such as Squalene and CoQ, for preventing ferroptosis-related disorders”, said Dr Ariati Aris, Scientific Affairs Specialist at PhytoGaia.
“This discovery adds to our scientific knowledge, highlighting the numerous health benefits linked to potent lipid peroxide scavengers like Squalene and CoQ10. If the antioxidant system is disrupted, it can lead to the excessive activation of ferroptosis. This opens up exciting opportunities for innovative dietary supplements or a well-balanced diet enriched with plant Squalene and CoQ10, aimed at maintaining cellular integrity and promoting overall well-being.”
