Noscapine derivative 428 suppresses ferroptosis through targeting GPX4.

ABSTRACT: Inhibiting ferroptosis represents a promising strategy to combat ferroptosis-related diseases. Here we show that 428, a selenide-containing noscapine derivative, effectively inhibits ferroptosis in various cell lines by enhancing the stability and activity of GPX4. TRIM41 was identified as a novel E3 ubiquitin ligase of GPX4 and 428 was demonstrated to bind to the selenocysteine residue Sec46 of GPX4 via the formation of a transient and reversible Se-Se bond, thereby blocking the interaction between GPX4 and TRIM41, stabilizing GPX4 and enhancing its activity. This unique dynamic covalent binding mode was preliminarily validated by structure-activity relationship analysis and molecular docking studies. Importantly, we demonstrated that 428 treatment alleviates bleomycin-induced pulmonary f

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC12433912 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature