Lysosomal lipid peroxidation

Lysosomal lipid peroxidation refers to the oxidative degradation of lipids within the lysosomal membrane, typically initiated by iron-dependent generation of reactive oxygen species that attack polyunsaturated fatty acids (PUFAs) in lysosomal and cellular membranes[3][5][7]. This process leads to the accumulation of lipid peroxides, resulting in increased lysosomal membrane permeability (LMP), leakage of lysosomal contents (such as hydrolytic enzymes and iron), and ultimately cell death via ferroptosis or other regulated cell death pathways[3][4][6]. Lysosomal lipid peroxidation has been recognized as a key initiator and amplifier of cell death, especially in contexts such as cancer (where immunogenic cell death is beneficial) or neurodegenerative disease (where it can be detrimental)[6][9]. Pharmacological inhibitors (e.g., Lyso-NBD-Pen) that localize to the lysosome and quench lipid radicals provide experimental evidence that this process can be selectively modulated, offering potential avenues for therapy and biomarker development[3].

Drugs act via radical trapping antioxidant mechanisms (e.g., Lyso-NBD-Pen suppresses the chain reaction of lipid radicals in the lysosome) or through iron chelation (e.g., salinomycin both triggers and can modulate the process via iron metabolism in lysosomes).