Lysosomal lipid peroxidation contributes to ferroptosis induction via lysosomal membrane permeabilization

Yuma Saimoto, Daiki Kusakabe, Kazushi Morimoto, Yuta Matsuoka, Eisho Kozakura, Nao Kato, Kayoko Tsunematsu, Tomohiro Umeno, Tamiko Kiyotani, Shota Matsumoto, Mieko Tsuji, Tasuku Hirayama, Hideko Nagasawa, Koji Uchida, Satoru Karasawa, Mirinthorn Jutanom and Ken-ichi Yamada ()
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Yuma Saimoto: Kyushu University
Daiki Kusakabe: Kyushu University
Kazushi Morimoto: Kyushu University
Yuta Matsuoka: Kyushu University
Eisho Kozakura: Kyushu University
Nao Kato: Kyushu University
Kayoko Tsunematsu: Kyushu University
Tomohiro Umeno: Showa Pharmaceutical University
Tamiko Kiyotani: Showa Pharmaceutical University
Shota Matsumoto: Showa Pharmaceutical University
Mieko Tsuji: Gifu Pharmaceutical University
Tasuku Hirayama: Gifu Pharmaceutical University
Hideko Nagasawa: Gifu Pharmaceutical University
Koji Uchida: The University of Tokyo
Satoru Karasawa: Showa Pharmaceutical University
Mirinthorn Jutanom: Kyushu University
Ken-ichi Yamada: Kyushu University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-58909-w

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