Mechanism of ferroptosis resistance in senescent cells uncovered

July 30, 2025

Lysosomal acidity as a key regulator of iron-dependent cell death

A collaborative research group from the Cancer Institute, Kyoto University, Kyushu University, Tokyo University of Pharmacy and Life Sciences, the RIKEN CSRS, the University of Tokyo, and Tokyo University of Science has elucidated why senescent cells are more resistant to ferroptosis, an iron- dependent form of cell death, than normal cells. Senescent cells promote various age-related pathologies, including cancer, through the creation of a chronic inflammatory microenvironment. Therefore, the findings of this study suggest a novel therapeutic strategy for diseases driven by senescent cells.

Although senescent cells accumulate iron intracellularly, they exhibit resistance to ferroptosis, an iron- dependent form of cell death. The research group discovered that lysosomes, which are organelles responsible for degrading cellular waste, are impaired in senescent cells due to a loss of acidity, then found this phenomenon is caused by reduced activity of the V-ATPase. Similar lysosomal dysfunction is known in pancreatic cancer cells, so the research group treated pancreatic cancer mouse models with the V-ATPase activator, which restored lysosomal acidity and significantly suppressed tumor progression. This study not only reveals a link between lysosomal dysfunction and ferroptosis resistance in senescent cells, but also suggests that modulating lysosomal acidity may offer a therapeutic strategy for age-related diseases, including treatment-resistant cancers 

 

Original article

Nature Communications　doi: 10.1038/s41467-025-61894-9

T. M. Loo, X. Zhou, Y. Tanaka, S. Sugawara, S. Yamauchi, H. Kawasaki, Y. Matsuoka, Y. Sugiura, S. Sakuma, Y. Yamanishi, S. Yotsumoto, K. Dodo, Y. Shirasaki, T. Kamatani, A. Takahashi,

"Senescence-associated lysosomal dysfunction impairs cystine deprivation-induced lipid peroxidation and ferroptosis".

Contact

Kosuke Dodo
Senior Research Scientist
Catalysis and Integrated Research Group