Programmed cell death

Cell biology

Biology

GPX4

Reactive oxygen species

Apoptosis

Cancer research

Biochemistry

Glutathione

Glutathione peroxidase

Genetics

In vivo

In vitro

Enzyme

Chemistry

Homocysteine

Cancer

Cancer cell

Nature Communications

Ferroptosis is a newly characterized form of regulated cell death mediated by iron-dependent accumulation of lipid reactive oxygen species and holds great potential for cancer therapy. However, the molecular mechanisms underlying ferroptosis remain largely elusive. In this study, we define an integrative role of DJ-1 in ferroptosis. Inhibition of DJ-1 potently enhances the sensitivity of tumor cells to ferroptosis inducers both in vitro and in vivo. Metabolic analysis and metabolite rescue assay reveal that DJ-1 depletion inhibits the transsulfuration pathway by disrupting the formation of the S-adenosyl homocysteine hydrolase tetramer and impairing its activity. Consequently, more ferroptosis is induced when homocysteine generation is decreased, which might be the only source of glutathione biosynthesis when cystine uptake is blocked. Thus, our findings show that DJ-1 determines the response of cancer cells to ferroptosis, and highlight a candidate therapeutic target to potentially improve the effect of ferroptosis-based antitumor therapy.

DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase