Lysosomal lipid peroxidation contributes to ferroptosis induction via lysosomal membrane permeabilization
Ferroptosis, a form of cell death instigated by iron-dependent lipid peroxidation reactions (LPO), is emerging as a promising therapeutic target for cancer. While the mechanisms governing LPO induction and suppression have gradually been unveiled, questions persist regarding the specific cellular location of LPO and the utilization of iron in driving cell death. A comprehensive understanding of these aspects holds significant potential for advancing therapeutic applications in disease management. Here, we show lysosomal LPO in the initiation of ferroptosis, leveraging the hidden abilities of fluorescent detection probes. Intra-lysosomal LPO triggers iron leakage, fostering cell-wide LPO by augmenting lysosomal membrane permeabilization (LMP). Conversely, cell lines with low susceptibility to ferroptosis do not exhibit LMP. This deficiency is rectified by the concurrent administration of chloroquine, leading to LMP induction and subsequent cell death. These findings underscore enhancing LMP induction efficacy as a strategic approach to surmount resistance to therapies in cancer.
Authors
- Yuma Saimoto (ORCID: https://orcid.org/0009-0002-6756-4399)
- Hideko Nagasawa (ORCID: https://orcid.org/0000-0002-7662-0762)
- Nao Kato (ORCID: https://orcid.org/0000-0003-4038-3387)
- Yuta Matsuoka (ORCID: https://orcid.org/0000-0001-9860-3851)
- Satoru Karasawa
- K Tsunematsu
- Tomohiro Umeno (ORCID: https://orcid.org/0000-0002-4342-2292)
- Kazushi Morimoto (ORCID: https://orcid.org/0000-0001-7698-9378)
- Daiki Kusakabe
- Kôji Uchida (ORCID: https://orcid.org/0000-0003-3894-5299)
- Mirinthorn Jutanom (ORCID: https://orcid.org/0009-0007-4535-1612)
- Tasuku Hirayama (ORCID: https://orcid.org/0000-0003-4541-7849)
- Shota Matsumoto (ORCID: https://orcid.org/0000-0002-8243-7163)
- Mieko Tsuji (ORCID: https://orcid.org/0000-0003-2072-2118)
- Ken‐ichi Yamada (ORCID: https://orcid.org/0000-0003-2100-8477)
- Tetsuya Kiyotani
- Eisho Kozakura
Institutions
- Kyushu University (JP)
- Tokyo University of Pharmacy and Life Sciences (JP)
- Gifu Pharmaceutical University (JP)
- Kyoto University (JP)
- Kyoto University Hospital (JP)
- The University of Tokyo (JP)
- Showa Pharmaceutical University (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1038/s41467-025-58909-w
- Citations
- 63
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 95.66
Funders
- Takeda Science Foundation
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science
- Core Research for Evolutional Science and Technology