RSL3 promotes PARP1 apoptotic functions by distinct mechanisms during ferroptosis.

ABSTRACT:

Background

The classical ferroptosis activator RSL3 targets enzymes with nucleophilic active sites, primarily acting on glutathione peroxidase 4 (GPX4) to trigger ferroptosis. Recent studies identify RSL3 as a potential pro-apoptotic agent. However, the mechanism by which RSL3 induces apoptosis during ferroptosis remains elusive. Poly(ADP-ribose) polymerase (PARP1) determines cell fate in response to DNA damage, where its loss or cleavage by activated caspase-3 induces apoptosis to attenuate tumor progression. We elucidate a novel mechanism underlying PARP1 regulation, encompassing both its caspase-dependent cleavage and full-length depletion during RSL3-mediated ferroptosis-apoptosis crosstalk.

Methods

To investigate the role of RSL3 during ferroptosis, we treated several c

SUBMITTER: Chen D 

PROVIDER: S-EPMC12492750 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature