ATF3 promotes erastin-induced ferroptosis by suppressing system Xc–

TLDR

The cystine/glutamate antiporter system Xc⁻ supplies cystine for glutathione synthesis, protecting cells from ferroptosis, and its inhibition by erastin depletes GSH and triggers lipid peroxidation, yet how system Xc⁻ is regulated during ferroptosis remains largely unknown. This study shows that the stress‑responsive transcription factor ATF3 promotes erastin‑induced ferroptosis. ATF3 binds the SLC7A11 promoter and represses its transcription in a p53‑independent manner, thereby down‑regulating system Xc⁻. Consequently, ATF3 suppresses system Xc⁻, depletes intracellular GSH, and enhances lipid peroxidation, adding ATF3 to the small group of proteins that regulate system Xc⁻ and ferroptosis.

Abstract

The amino acid antiporter system Xc- is important for the synthesis of glutathione (GSH) that functions to prevent lipid peroxidation and protect cells from nonapoptotic, iron-dependent death (i.e., ferroptosis). While the activity of system Xc- often positively correlates with the expression level of its light chain encoded by SLC7A11, inhibition of system Xc- activity by small molecules (e.g., erastin) causes a decrease in the intracellular GSH level, leading to ferroptotic cell death. How system Xc- is regulated during ferroptosis remains largely unknown. Here we report that activating transcription factor 3 (ATF3), a common stress sensor, can promote ferroptosis induced by erastin. ATF3 suppressed system Xc-, depleted intracellular GSH, and thereby promoted lipid peroxidation induced by erastin. ATF3 achieved this activity through binding to the SLC7A11 promoter and repressing SLC7A11 expression in a p53-independent manner. These findings thus add ATF3 to a short list of proteins that can regulate system Xc- and promote ferroptosis repressed by this antiporter.