Recharacterization of the Tumor Suppressive Mechanism of RSL3 Identifies the Selenoproteome as a Druggable Pathway in Colorectal Cancer.

ABSTRACT: Ferroptosis is a nonapoptotic form of cell death driven by iron-dependent lipid peroxide accumulation. Colorectal cancer cells feature elevated intracellular iron and reactive oxygen species that heighten ferroptosis sensitivity. The ferroptosis inducer (S)-RSL3 [(1S,3R)-RSL3] is widely described as a selective inhibitor of the selenocysteine-containing enzyme (selenoprotein) glutathione peroxidase 4 (GPX4), which detoxifies lipid peroxides using glutathione. However, through chemical controls using the (R) stereoisomer of RSL3 [(1R,3R)-RSL3] that does not bind GPX4, combined with inducible genetic knockdowns of GPX4 in colorectal cancer cell lines, we revealed in this study that GPX4 dependency does not always align with (S)-RSL3 sensitivity, thereby questioning the current characterizati

SUBMITTER: DeAngelo SL 

PROVIDER: S-EPMC12402965 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature