Regulation of ferroptosis by inter-organellar metabolic signaling network

Abstract

Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation, and is therefore intrinsically coupled to cellular redox metabolism. Progression of ferroptosis is regulated by an integrated network of metabolic signaling pathways that involve inter-organellar communication. In this Review, we synthesize recent progress in the field that has advanced our understanding of the metabolic determinants of ferroptosis. We discuss key metabolites which participate in the execution and prevention of ferroptosis, describe major signaling axes that impinge on regulating these metabolic activities to determine cellular ferroptosis sensitivity, and highlight how compartmentalized metabolism within and across distinct intracellular organelles collectively shape ferroptosis progression. Together, this Review aims to provide a framework that unifies metabolic state, signaling plasticity and organellar cooperation as a mechanistic basis of ferroptosis, underscoring its implications in the pathogenesis of various diseases including cancer.