Redox Biology (Feb 2025)
Targeting p62 by sulforaphane promotes autolysosomal degradation of SLC7A11, inducing ferroptosis for osteosarcoma treatment
- Qiuming Zou,
- Xiaofeng Zhou,
- Jianqin Lai,
- Haixia Zhou,
- Jinxuan Su,
- Zhijing Zhang,
- Xiaosong Zhuang,
- Lili Liu,
- Ruijie Yuan,
- Sijia Li,
- Siyu Yang,
- Xinyi Qu,
- Jiezhu Feng,
- Yongqi Liu,
- Zisheng Li,
- Shiting Huang,
- Zhi Shi,
- Yu Yan,
- Zhiming Zheng,
- Wencai Ye,
- Qi Qi
Affiliations
- Qiuming Zou
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Xiaofeng Zhou
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Jianqin Lai
- Department of Gastrointestinal Surgery, Guangzhou First People's Hospital, Guangzhou, 510180, China
- Haixia Zhou
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Jinxuan Su
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Zhijing Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Xiaosong Zhuang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Lili Liu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Center for Bioactive Natural Molecules and Innovative Drugs Research, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
- Ruijie Yuan
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Sijia Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Siyu Yang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Xinyi Qu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Jiezhu Feng
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Yongqi Liu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Zisheng Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Shiting Huang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China
- Zhi Shi
- Department of Cell Biology & Institute of Biomedicine, Guangdong Provincial Biotechnology & Engineering Technology Research Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Genomic Medicine Engineering Research Center of Ministry of Education, MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
- Yu Yan
- Functional Experimental Teaching Center, School of Medicine, Jinan University, Guangzhou, 510632, China; Corresponding author.
- Zhiming Zheng
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China; Corresponding authors.
- Wencai Ye
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Center for Bioactive Natural Molecules and Innovative Drugs Research, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China; Corresponding author.
- Qi Qi
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China; Corresponding authors.
- Journal volume & issue
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Vol. 79
p. 103460
Abstract
Osteosarcoma (OS) is the most prevalent malignant bone tumor in children and adolescents worldwide. Identification of novel therapeutic targets and development of targeted drugs are one of the most feasible strategies for OS treatment. Ferroptosis, a recently discovered mode of programmed cell death, has been implicated as a potential strategy for cancer therapy. Sulforaphane (SFN), the main bioactive compound derived from cruciferous vegetables, has shown potential anti-cancer effects with negligible toxicity. However, the role of ferroptosis in the effect of SFN on OS remains unknown. In the present study, we found that SFN acted as a potent ferroptosis inducer in OS, which was demonstrated by various inhibitors of cell death. The SFN-induced ferroptotic cell death was characterized by elevated ROS levels, lipid peroxidation, and GSH depletion, which was dependent on decreased levels of SLC7A11. Mechanically, SFN directly targeted p62 protein and enhanced p62/SLC7A11 protein-protein interaction, thereby promoting the lysosomal degradation of SLC7A11 and triggering ferroptosis. Notably, both subcutaneous and intratibial OS models in nude mice confirmed the ferroptosis associated anti-cancer efficacy of SFN in vivo. Hence, our findings demonstrate that SFN exerts its anti-cancer effects through inducing SLC7A11-dependent ferroptosis in OS, providing compelling evidence for the application of SFN in OS treatment.
