Lysosome: a critical hub for ferroptosis regulation

Ferroptosis is an iron-dependent programmed cell death that involves lipid peroxidation. Ferroptosis represents a critical process underlying tumorigenesis and multiple pathological disorders. Recently, lysosomes have been found to orchestrate ferroptotic signaling, linking iron metabolism, oxidative homeostasis, and selective autophagy. Furthermore, lysosomal membrane disruption leads to the release of intraluminal iron and cathepsins, thereby facilitating ferroptotic damage, whereas lysosomal exocytosis acts in the opposite direction to limit ferroptosis. Therefore, pharmacological modulation of lysosomal activities could be used to treat drug-resistant tumors or protect normal tissues against ferroptosis-related injuries. In this review, we summarize how lysosomes control ferroptosis, focusing on the regulation through lysosomal contents, pH, degradation processes, and exocytosis. We also discuss possible therapeutics that target lysosomes to modulate ferroptosis-associated diseases.