RNF126-mediated ubiquitination of FSP1 affects its subcellular localization and ferroptosis

Abstract

Medulloblastoma (MB) is a prevalent malignant brain tumor among children, which can be classi ed into four primary molecular subgroups. Group 3 MB (G3-MB) is known to be highly aggressive and associated with a poor prognosis, necessitating the development of novel and effective therapeutic interventions.Ferroptosis, a regulated form of cell death induced by lipid peroxidation, has been identi ed as a natural tumor suppression mechanism in various cancers. Nevertheless, the potential role of ferroptosis in the treatment of G3-MB remains unexplored. In this study, we demonstrate that RNF126 acts as an antiferroptotic gene by interacting with ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) and ubiquitinating FSP1 at the 4KR-2 sites. Additionally, the deletion of RNF126 reduces the subcellular localization of FSP1 in the plasma membrane, resulting in an increase in the CoQ/CoQH2 ratio in G3-MB.The RNF126-FSP1-CoQ10 pathway plays a pivotal role in suppressing phospholipid peroxidation and ferroptosis both in vivo and in vitro. Our ndings indicate that RNF126 regulates G3-MB sensitivity to ferroptosis by ubiquitinating FSP1, which provides new evidence for the potential G3-MB therapy. Highlights 1. RNF126 is a potent ferroptosis suppressor.2. RNF126 modulates the subcellular localization of FSP1 through ubiquitinating FSP1.3. RNF126-FSP1-CoQ10 pathway is a potential therapy target for G3-MB.