Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, China.
National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, 430074, China.
Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosis
Ferroptosis is a recently-defined tumor suppression mechanism, but the sensitivity of many tumorigenic cells to ferroptosis is limited by their deficient expression of acyl-CoA synthetase long-chain family member 4 (ACSL4). Here, we report the discovery of a photosensitizer, namely TPCI, which can evoke ACSL4-independent ferroptosis of cancer cells in photodynamic therapy. Through co-localization with 12-lipoxygenase (ALOX12) in multiple subcellular organelles, TPCI activates ALOX12 to generate lipid reactive oxygen species in large quantity and trigger cell ferroptosis. Intriguingly, confining TPCI exclusively in lysosomes switches the cell death from ferroptosis to apoptosis. More strikingly, the ferroptosis mediated by TPCI-induced ALOX12 activation does not require the participation of ACSL4. Therefore, our study identifies TPCI as the first ALOX12 activator to induce ferroptosis independent of ACSL4, which renders a viable therapeutic approach on the basis of distinct ferroptosis of cancer cells, regardless their ACSL4 expressions.
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