The lysosomal iron rheostat: Orchestrating ferroptosis in cancer plasticity

Iron is indispensable for cellular metabolism yet potentially cytotoxic, making its intracellular handling a fundamental determinant of cell fate decisions. The endo-lysosomal system has recently emerged as a central iron rheostat that integrates transferrin uptake, ferritinophagy, and lysosomal iron export to control iron bioavailability for mitochondria and other iron-dependent pathways. Growing studies further show that lysosomal iron is not merely permissive for ferroptosis but can directly initiate lipid damage through localized iron activation, lysosomal lipid peroxidation, and lysosomal membrane permeabilization. At the same time, emerging studies on organelle contact sites reveal that ferroptosis arises from the failure of a coordinated multi-organellar communication system, in which lysosomes, the endoplasmic reticulum, and mitochondria exchange iron, lipids, and redox signals in an effort to metabolically adapt to stress. This perspective is particularly relevant to drug-tolerant persisters and mesenchymal cancer cell states, which rely on rewired lysosomal iron trafficking to sustain plasticity while becoming highly susceptible to ferroptosis. In this minireview, we discuss emerging insights into the spatial organization of iron metabolism and propose a model in which ferroptosis sensitivity depends on the intracellular routing, chemical reactivity, and release dynamics of iron, highlighting lysosomal iron handling as a key therapeutic vulnerability in minimal residual disease.