Loss of LPR8 Reduces GPX4 Levels, Resulting in Ferroptosis Sensitivity

Ferroptosis, a regulated form of necrotic cell death, can be prevented by the activity of GPX4, a glutathione-dependent peroxidase and selenoprotein that previous studies have indicated can induce ferroptosis when inhibited. However, cancer cells show variability in their sensitivity to ferroptosis, and the mechanisms that cells use to prevent ferroptosis and regulate GPX4 remain undefined. Thus, Li and colleagues used a chemical–genetic screen and identified the lipoprotein receptor LRP8 as a regulator of ferroptosis resistance across a broad range of cancer types. A robust interaction was observed between LRP8 and glutathione metabolism and selenium-related factors such as GPX4 and selenocysteine (SEC) synthesis, notable as LRP8 serves as a receptor for the SEC-rich protein selenoprotein P (SEPP1), which when broken down releases selenium. Knockout of LRP8 decreases selenium levels by approximately 60%, with addition of selenite (Se), a form of selenium taken up independently of LRP8, rescuing this reduction and ferroptosis sensitivity. Moreover, LRP8 knockout significantly reduced GPX4 levels as well as levels of some other selenoproteins, which could also be rescued by Se addition but not by ferroptosis inhibitors, with this loss being reversed only upon reexpression of LRP8 mutants that are able to bind to SEPP1. Additionally, normal epithelial cells lines did not demonstrate these alterations to GPX4 expression, suggesting a cancer cell–specific phenotype. Furthermore, counter to the prevailing selenoprotein regulatory hierarchy, GPX4 was indicated to be one of the initial proteins reduced after selenium depletion, with studies investigating the role of GPX4 in mediating LRP8 knockout ferroptosis sensitivity revealing that limited selenium due to LRP8 knockout reduces GPX4 and subsequent ferroptosis. Mechanistically, the loss of GPX4 was induced by abrogated translation caused by ribosome stalling and premature translation termination leading to proteasomal clearance. In summary, these findings indicate LRP8 as a factor in cancer cell ferroptosis resistance, which mediates its effects through selenium and GPX4 translation, and suggest the targeting of selenoproteins to sensitize cancer cells to ferroptosis.

Li Z, Ferguson L, Deol KK, Roberts MA, Magtanong L, Hendricks JM, et al. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. Nat Chem Biol 2022;18:751–61.

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