Non-enzymatic lipid peroxidation initiated by photodynamic therapy drives a distinct ferroptosis-like cell death pathway
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Updated: Oct 29, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Sufang Shui1, Zenglu Zhao1, Hao Wang1
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Abstract:
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.
Insights
Photodynamic therapy (PDT) triggers a novel cell death called liperoptosis by directly oxidizing lipids, bypassing ACSL4. This ferroptosis-like cell death is effective against resistant cancer cells and shows promise in vivo.
Area of Science:
- Cellular Biology
- Cancer Research
- Biochemistry
Background:
- Ferroptosis, a regulated cell death, is typically induced by the failure of the glutathione (GSH)-glutathione peroxidase 4 (GPX4) system, leading to lipid peroxidation.
- Enzymes like acyl-CoA synthetase long chain family member 4 (ACSL4) are crucial in regulating polyunsaturated fatty acid (PUFA) metabolism during ferroptosis.
Purpose of the Study:
- To investigate the mechanism of cell death induced by photodynamic therapy (PDT).
- To explore the potential of PDT in triggering ferroptosis-like cell death, especially in resistant cancer cells.
Main Methods:
- Investigated the effects of exogenous oxygen radicals generated by PDT on PUFAs and cellular GSH levels.
- Analyzed the involvement of lipoxygenase (ALOXs) and ACSL4 in PDT-induced cell death.
- Examined iron metabolism changes and the role of the mitochondrial calcium and iron uniporter (MCU) in PDT-induced cell death.
- Utilized a mouse xenograft model with the photosensitizer Verteporfin to assess PDT's anti-tumor efficacy.
Main Results:
- PDT directly peroxidizes PUFAs, initiating lipid autoxidation and GSH depletion, independent of ALOXs and ACSL4.
- PDT-induced ferroptosis-like cell death, termed 'liperoptosis', is effective in cancer cells resistant to canonical ferroptosis inducers.
- PDT alters iron metabolism by decreasing cytosolic labile iron, with MCU inhibition preventing PDT-induced cell death.
- In vivo, PDT with Verteporfin inhibited tumor growth by inducing liperoptosis in a mouse xenograft model.
Conclusions:
- PDT induces a distinct form of ferroptosis-like cell death (liperoptosis) through direct lipid peroxidation, offering a new therapeutic strategy.
- Liperoptosis is effective against ferroptosis-resistant cancers and involves a unique iron metabolism pathway regulated by MCU.
- PDT demonstrates potential for site-specific cancer treatment by triggering liperoptosis, warranting further investigation into its immunomodulatory effects.
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