Nucleotide metabolism is linked to cysteine availability.

Area of Science:

• Cellular Metabolism
• Oxidative Stress
• Biochemistry

Background:

• Erastin inhibits system x_c^-, causing cysteine depletion and ferroptosis, a form of oxidative cell death.
• Ferroptosis inducers are known to impact cellular metabolism, but these effects are not well-characterized.
• Understanding metabolic alterations is crucial for exploring ferroptosis mechanisms and therapeutic strategies.

Purpose of the Study:

• To systematically investigate the global metabolic impact of erastin in cultured cells.
• To compare erastin's metabolic profile with other ferroptosis inducers (RAS-selective lethal 3) and in vivo cysteine deprivation.
• To identify key metabolic pathways affected by ferroptosis and assess the role of nucleotide metabolism.

Main Methods:

• Metabolomic analysis of cultured cells treated with erastin, RAS-selective lethal 3, or subjected to cysteine deprivation.
• Comparison of metabolic profiles across different ferroptosis induction methods.
• Functional assays assessing cell proliferation and viability upon nucleoside supplementation.

Main Results:

• Erastin treatment and cysteine deprivation induced common alterations in nucleotide and central carbon metabolism.
• Nucleoside supplementation rescued cell proliferation in certain cysteine-deprived conditions, indicating the importance of nucleotide metabolism.
• While GPX4 inhibition mimicked cysteine deprivation's metabolic profile, nucleoside treatment did not rescue viability under RAS-selective lethal 3 treatment, suggesting context-dependent roles.

Conclusions:

• Ferroptosis induction significantly impacts global cellular metabolism, with notable changes in nucleotide and central carbon pathways.
• Nucleotide metabolism is a critical target affected by cysteine deprivation during ferroptosis.
• The relevance of observed metabolic changes varies depending on the specific ferroptosis inducer and cellular context.