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

Tze Mun Loo, Xiangyu Zhou, Yoko Tanaka, Sho Sugawara, Shota Yamauchi, Hiroko Kawasaki, Yuta Matsuoka, Yuki Sugiura, Shinya Sakuma, Yoko Yamanishi, Satoshi Yotsumoto, Kosuke Dodo, Yoshitaka Shirasaki, Takashi Kamatani and Akiko Takahashi ()
Additional contact information
Tze Mun Loo: Japanese Foundation for Cancer Research
Xiangyu Zhou: Japanese Foundation for Cancer Research
Yoko Tanaka: Japanese Foundation for Cancer Research
Sho Sugawara: Japanese Foundation for Cancer Research
Shota Yamauchi: Japanese Foundation for Cancer Research
Hiroko Kawasaki: Japanese Foundation for Cancer Research
Yuta Matsuoka: Kyoto University Graduate School of Medicine
Yuki Sugiura: Kyoto University Graduate School of Medicine
Shinya Sakuma: Kyushu University
Yoko Yamanishi: Kyushu University
Satoshi Yotsumoto: Tokyo University of Pharmacy and Life Sciences
Kosuke Dodo: RIKEN Center for Sustainable Resource Science
Yoshitaka Shirasaki: The University of Tokyo
Takashi Kamatani: Institute of Science Tokyo
Akiko Takahashi: Japanese Foundation for Cancer Research

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-61894-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61894-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-61894-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().