Ferroptosis is a form of regulated cell death characterized by iron-dependent accumulation of lipid peroxidation and lethal reactive oxygen species(ROS).To date,misregulated ferroptosis has been implicated in several types of cancers,and ferroptosis inducers can be used to promote ferroptosis in tumor cells and play an anti-tumor role.However,the specificity and efficacy of ferroptosis inducers remain unsatisfactory.Here,a new mitochondria-targeted photosensitizer(PS)with aggregation-induced emission(AIE)characteristic named TCSVP was designed,which efficiently generates ROS in mitochondria after light ex-posure.TCSVP administration significantly sensitizes tumor cells to ferroptosis inducer(RSL3)-mediated cell death by spe-cifically and light-dependently triggering a moderate ROS generation in vitro and in vivo.Mechanically,the expression levels of ferroptosis related proteins Acyl-CoA synthetase long-chain family member 4(FACL4/ACSL4)and cyclooxygenase-2(COX2)were increased in TCSVP/RSL3-treated cells after light exposure,coupled with decreased Glutathione peroxidase 4(GPX4)activity and excessive malondialdehyde(MDA)accumulation.This study declared that light-induced moderate ROS generation within mitochondria in cancer cells by AIE-PS can be used to enhance the specificity and efficacy of ferroptosis inducers,bringing a new synergistic strategy for tumor intervention.

Fudan University Shanghai Cancer Center Shanghai Medical College,Fudan University,Shanghai 200032,China;Department of Chemistry,Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction,Institute for Advanced Study,State Key Laboratory of Molecular Nanoscience,Division of Life Science,and Department of Chemical and Biological Engineering,The Hong Kong University of Science and Technology,Hong Kong 999077,China;Institute of Metabolism and Integrative Biology,Fudan University,Shanghai 200433,China;The International Cooperation Laboratory on Signal Transduction,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai 200438,China;National Center for Liver Cancer Shanghai 200441,China;Shenzhen Institute of Aggregate Science and Technology,School of Science and Engineering,The Chinese University of Hong Kong,Shenzhen 518172,China;AIE Institute,Guangzhou Development District,Guangzhou 510530,China

[1]Shan Wang;Chao Chen;Jianmin Wu;Jianyu Zhang;Jacky W.Y.Lam;Hongyang Wang;Lei Chen;Ben Zhong Tang-.A mitochondria-targeted AIE photosensitizer for enhancing specificity and efficacy of ferroptosis inducer)[J].中国科学:化学（英文版）,2022(05):870-876

misregulated,TCSVP,cifically,FACL4

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