2025-07-29 がん研究会がん研究所
図. 老化細胞のリソソームを酸性化させることでフェロトーシス感受性が高くなる
<関連情報>
- https://www.jfcr.or.jp/laboratory/news/11502.html
- https://www.nature.com/articles/s41467-025-61894-9
老化関連リソソーム機能障害は、システイン欠乏誘発性脂質過酸化とフェロプトーシスを阻害する 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 & Akiko Takahashi
Nature Communication Published:29 July 2025
DOI:https://doi.org/10.1038/s41467-025-61894-9
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.
