2026-11-04 京都⼤学
老化細胞では、反応性の高い二価鉄（Fe²⁺）がリソソームに蓄積し、老化変化を促進します。一方、コレステロールがリソソーム膜を補強して鉄による障害を防ぎ、酸化されやすい脂質（PUFA）は脂肪滴に隔離されます。こうして「攻撃：鉄」と「標的：脂質」を細胞内で分離することで、老化細胞は鉄依存的な細胞死・フェロトーシスを回避して生き残ります。（作成者：簗取いずみ、生成AI：Google Gemini [Imagen 3]）
＜関連情報＞
- https://www.kyoto-u.ac.jp/ja/research-news/2026-11-04
- https://link.springer.com/article/10.1038/s44318-026-00939-1
コレステロールによる防御を介した⼆価鉄のリソソームへの安全な隔離が、細胞⽼化とフェロトーシス抵抗性を促進する Safe lysosomal sequestration of ferrous iron is mediated via cholesterol shielding and drives senescence and ferroptosis resistance
Izumi Yanatori, Tasuku Hirayama, Raku Son, Yasuhiro Murakawa, Yuta Matsuoka, Yuki Sugiura, Masato Niwa, Tatsuya Katsuno, Masahiko Tsujimoto, Hiroyuki Yasui, Atsuyasu Sato, Makoto Nakanishi & Kazuhiro Iwai
The EMBO Journal Published:02 November 2026
DOI:https://doi.org/10.1038/s44318-026-00939-1
Abstract
Iron accumulation is a conserved hallmark of cellular as well as organismal aging, yet its mechanistic role in senescence remains largely elusive. Here we show that the accumulation of ferrous iron (Fe2+) in lysosomes, a unique feature of senescent cells, is crucial for the induction of multiple senescence-associated phenotypes. Intriguingly, we found that this lysosomal Fe2+ sequestration is rendered “safe” by a dual metabolic adaptation that confers robust resistance to ferroptosis. First, Fe2+ accumulation triggers lysosomal alkalinization and subsequent cholesterol accumulation, which reinforces the lysosomal membrane against permeabilization. Second, senescent cells partition polyunsaturated fatty acids into lipid droplets, thereby depleting these ferroptosis-prone substrates from cellular membranes. Our findings establish that such cholesterol-enabled safe sequestration of Fe2+ serves as a central modulator linking senescence-associated remodeling to ferroptosis resistance. Modulating this lysosomal iron-centered pathway may provide new opportunities to target and control the behavior of senescent cells.
