Nα-Terminal Acetylation Meets Ferroptosis via N-Degron Pathway.

Abstract

Cell death can occur through programmed self-destruction, internal sabotage, accidental damage, or immune cell-mediated killing (Green, 2024). Among these, ferroptosis is a regulated, sabotage-type of cell death driven triggered by excessive lipid peroxidation, mostly involving iron, due to imbalances in nutrient, redox, and lipid metabolism (Berndt et al., 2024; Dixon et al., 2012; Green, 2024). Under mild lipid peroxidation, anti-ferroptosis effectors can activate antioxidant defenses, repair cellular damage, or maintain redox balance. However, when lipid peroxidation exceeds a critical threshold, pro-ferroptosis effectors more effectively shift to promoting ferroptosis (Berndt et al., 2024). Furthermore, at critical points, cells are likely to activate both survival and ferroptosis pathways simultaneously, temporarily resisting ferroptosis and sustaining the metastable state between ferroptosis and survival. Supporting this, our recent study on the Na-terminal (Nt-) acetylation-mediated protein degradation system (the Ac/N-degron pathway) suggests a plausible mechanism that concurrently manages these opposing pro-ferroptotic and anti-ferroptotic effectors, potentially influencing cell fate (Figure 1) (Yang et al., 2024).