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Shui, S.* ; Zhao, Z.* ; Wang, H.* ; Conrad, M. ; Liu, G.*

Non-enzymatic lipid peroxidation initiated by photodynamic therapy drives a distinct ferroptosis-like cell death pathway.

Redox Biol. 45:102056 (2021)

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Ferroptosis is primarily triggered by a failure of the glutathione (GSH)-glutathione peroxidase 4 (GPX4) reductive system and associated overwhelming lipid peroxidation, in which enzymes regulating polyunsaturated fatty acid (PUFA) metabolism, and in particular acyl-CoA synthetase long chain family member 4 (ACSL4), are central. Here, we found that exogenous oxygen radicals generated by photodynamic therapy (PDT) can directly peroxidize PUFAs and initiate lipid autoxidation, coinciding with cellular GSH depletion. Different from canonical ferroptosis induced by RSL3 or erastin, PDT-initiated lipid peroxidation and ferroptotis-like cell death is independent of lipoxygenase (ALOXs) and ACSL4. Especially, this form of cell death modality can be triggered in malignant cells insensitive to or acquired resistance to canonical ferroptosis inducers. We also observed a distinct iron metabolism pathway in this PDT-triggered cell death modality, in which cytosolic labile iron is decreased probably due to its relocation to mitochondria. Inhibition of the mitochondrial Ca²⁺ and Fe²⁺ uniporter (MCU) effectively prevented PDT-triggered lipid peroxidation and subsequent cell death. Therefore, we tentatively term this distinct ferroptosis-like cell death as liperoptosis. Moreover, using the clinically approved photosensitizer Verteporfin, PDT inhibited tumor growth through inducing prevailing ferroptosis-like cell death in a mouse xenograft model. With its site-specific advantages, these findings highlight the value of using PDT to trigger lipid peroxidation and ferroptosis-like cell death in vivo, and will benefit exploring the exact molecular mechanism of immunological effects of PDT in cancer treatment.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cell Death ; Ferroptosis ; Liperoptosis ; Lipid Peroxidation ; Pdt; Oxidative Stress; Cancer-cells; Iron; Lysosomes; Membrane; Translocation; Purification; Mitochondria; Degradation; Hypericin

ISSN (print) / ISBN 2213-2317

e-ISSN 2213-2317

Journal Redox Biology

Quellenangaben Volume: 45, Article Number: 102056

Publisher Elsevier

Publishing Place Amsterdam [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Metabolism and Cell Death (MCD)

Grants National Natural Science Foundation of China
Deutsche Forschungsgemeinschaft
German Federal Ministry of Education and Research (BMBF) VIP + program NEUROPROTEKT
Ministry of Science and Higher Education of The Russian Federation
European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme