Molecules. 2026 Jul 06. pii: 2373. [Epub ahead of print]31(13):
Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation and membrane damage, with broad relevance to human disease. Accumulating evidence suggests that ferroptosis is governed by coordinated organelle-level regulation, among which lysosomes have emerged as central hubs. By controlling endolysosomal iron processing, transport, and degradation pathways, lysosomes shape the intracellular distribution and reactivity of iron, thereby modulating iron-driven lipid peroxidation. The acidic, iron-rich microenvironment and limited local antioxidant capacity render lysosomal membranes highly susceptible to oxidative injury, positioning lysosomes as initiation and amplification sites of lipid peroxidation. Meanwhile, lysosome-dependent selective autophagy pathways actively remodel iron homeostasis, lipid metabolism, and cellular antioxidant defenses, thereby dynamically modulating ferroptotic sensitivity. Mitochondria-lysosome crosstalk further redistributes iron, reactive oxygen species, and lipid substrates, linking lysosomal activity to interorganelle control of ferroptosis. Lysosomal stress-responsive signaling also coordinates metabolic adaptation and redox control. This review summarizes and integrates current evidence on lysosome-centered mechanisms that organize iron metabolism, lipid peroxidation, selective autophagy, organelle crosstalk, and stress-responsive signaling during ferroptosis, and further discusses their disease-specific roles, therapeutic potential, and translational challenges.
Keywords: autophagy; ferroptosis; iron metabolism; lysosomes; oxidative stress