Ferroptosis is a form of programmed cell death driven by iron accumulation and involving extensive lipid peroxidation as the kill mechanism. Senescent cells accumulate with age to cause tissue dysfunction and are resistant to programmed cell death. Most present approaches to the selective destruction of senescent cells as a form of therapy involve some form of sabotage of one or more programmed cell death resistance mechanisms. Here, researchers show that senescent cells both accumulate iron and resist ferroptosis, which suggests potential targets for novel forms of senolytic drug capable of selectively destroying senescent cells with minimal harm to normal cells.
Senescent cells, characterized by irreversible cell cycle arrest and inflammatory factor secretion, promote various age-related pathologies. Senescent cells exhibit resistance to ferroptosis, a form of iron-dependent cell death; however, the underlying mechanisms remain unclear. Here, we discovered that lysosomal acidity was crucial for lipid peroxidation and ferroptosis induction by cystine deprivation. In senescent cells, lysosomal alkalinization causes the aberrant retention of ferrous iron in lysosomes, resulting in resistance to ferroptosis.
Treatment with the V-ATPase activator EN6 restored lysosomal acidity and ferroptosis sensitivity in senescent cells. A similar ferroptosis resistance mechanism involving lysosomal alkalinization was observed in pancreatic cancer cell lines. EN6 treatment prevented pancreatic cancer development in xenograft and Kras mutant mouse models. Our findings reveal a link between lysosomal dysfunction and the regulation of ferroptosis, suggesting a therapeutic strategy for the treatment of age-related diseases.
Link: https://doi.org/10.1038/s41467-025-61894-9
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