Safe lysosomal sequestration of ferrous iron is mediated via cholesterol shielding and drives senescence and ferroptosis resistance
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 (Fe 2+ ) in lysosomes, a unique feature of senescent cells, is crucial for the induction of multiple senescence-associated phenotypes. Intriguingly, we found that this lysosomal Fe 2+ sequestration is rendered “safe” by a dual metabolic adaptation that confers robust resistance to ferroptosis. First, Fe 2+ 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 Fe 2+ 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.
Authors
- Raku Son (ORCID: https://orcid.org/0000-0002-9250-9474)
- Hiroyuki Yasui (ORCID: https://orcid.org/0000-0003-3317-3947)
- Yasuhiro Murakawa (ORCID: https://orcid.org/0000-0002-5415-1352)
- Makoto Nakanishi (ORCID: https://orcid.org/0000-0002-6707-3584)
- Masahiko Tsujimoto (ORCID: https://orcid.org/0000-0003-4052-3378)
- Kazuhiro Iwaï (ORCID: https://orcid.org/0000-0001-5620-5951)
- Masato Niwa
- Yuki Sugiura (ORCID: https://orcid.org/0000-0002-6983-8958)
- Tatsuya Katsuno (ORCID: https://orcid.org/0000-0002-0395-4382)
- Tasuku Hirayama (ORCID: https://orcid.org/0000-0003-4541-7849)
- Izumi Yanatori (ORCID: https://orcid.org/0000-0002-1945-5473)
- Atsuyasu Sato (ORCID: https://orcid.org/0000-0001-8068-9984)
- Yuta Matsuoka
Institutions
- Gifu Pharmaceutical University (JP)
- Keio University (JP)
- Kyoto University (JP)
- Kyoto Pharmaceutical University (JP)
- Kyoto University Hospital (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- Center for Anatomical Studies, Graduate School of Medicine, Kyoto University (JP)
- Institute for the Advanced Study of Human Biology, Kyoto University (JP)
- Center for Cancer Immunotherapy and Immunobiology, Kyoto University (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Keio University Human Biology-Microbiome-Quantum Research Center (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2026-11-02
- DOI
- https://doi.org/10.1038/s44318-026-00939-1
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Agency for Medical Research and Development
- Takeda Medical Research Foundation
- Japan Society for the Promotion of Science
- Core Research for Evolutional Science and Technology
- Precursory Research for Embryonic Science and Technology
- Fusion Oriented REsearch for disruptive Science and Technology