Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability

The selenoprotein glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid peroxides into nontoxic lipid alcohols. GPX4 has emerged as a promising therapeutic target for cancer treatment, but some cancer cells are resistant to ferroptosis triggered by GPX4 inhibition. Using a chemical-genetic screen, we identify LRP8 (also known as ApoER2) as a ferroptosis resistance factor that is upregulated in cancer. Loss of LRP8 decreases cellular selenium levels and the expression of a subset of selenoproteins. Counter to the canonical hierarchical selenoprotein regulatory program, GPX4 levels are strongly reduced due to impaired translation. Mechanistically, low selenium levels result in ribosome stalling at the inefficiently decoded GPX4 selenocysteine UGA codon, leading to ribosome collisions, early translation termination and proteasomal clearance of the N-terminal GPX4 fragment. These findings reveal rewiring of the selenoprotein hierarchy in cancer cells and identify ribosome stalling and collisions during GPX4 translation as ferroptosis vulnerabilities in cancer.

Automated summary

The study identifies LRP8 as a ferroptosis resistance factor that is upregulated in cancer cells. The loss of LRP8 leads to decreased cellular selenium levels and reduces the expression of a subset of selenoproteins, including GPX4. Mechanistically, low selenium levels cause ribosome stalling and collisions during GPX4 translation, resulting in reduced levels of GPX4 and increased vulnerability to ferroptosis in cancer cells.