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LncFASA promotes cancer ferroptosis via modulating PRDX1 phase separation

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Abstract

Ferroptosis, a unique type of non-apoptotic cell death resulting from iron-dependent lipid peroxidation, has a potential physiological function in tumor suppression, but its underlying mechanisms have not been fully elucidated. Here, we report that the long non-coding RNA (lncRNA) LncFASA increases the susceptibility of triple-negative breast cancer (TNBC) to ferroptosis. As a tumor suppressor, LncFASA drives the formation of droplets containing peroxiredoxin1 (PRDX1), a member of the peroxidase family, resulting in the accumulation of lipid peroxidation via the SLC7A11-GPX4 axis. Mechanistically, LncFASA directly binds to the Ahpc-TSA domain of PRDX1, inhibiting its peroxidase activity by driving liquid-liquid phase separation, which disrupts intracellular ROS homeostasis. Notably, high LncFASA expression indicates favorable overall survival in individuals with breast cancer, and LncFASA impairs the growth of breast xenograft tumors by modulating ferroptosis. Together, our findings illustrate the crucial role of this lncRNA in ferroptosis-mediated cancer development and provide new insights into therapeutic strategies for breast cancer.

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Acknowledgement

This work was supported by the National Science Fund for Distinguished Young Scholars (32225014), the National Key Research and Development Program of China (2021YFC2700903), the National Natural Science Foundation of China (81672791, 81872300, 82071567), Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China (LR18C060002), and “Lingyan” R&D Research and Development Project (2023C03023). We thank Prof. X.L. and S.-F.X. (Westlake University) for assistance with protein MS analysis. We thank the First People’s Hospital of Huzhou (Huzhou, China) for the support of clinical breast cancer samples. We thank Prof. J.-R.P., Prof. J.L., B.-C.S., and X.-Y.H. for assistance with this study.

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Authors and Affiliations

  1. MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China

    Xiao Fan, Fangzhou Liu, Ying Wang, Yu Chen, Chengyu Shi, Xinwan Su, Manman Tan, Qingfeng Yan, Jianzhong Shao & Aifu Lin

  2. Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou, 310009, China

    Xiao Fan, Fangzhou Liu & Aifu Lin

  3. Cancer Center, Zhejiang University, Hangzhou, 310058, China

    Xiao Fan, Fangzhou Liu & Aifu Lin

  4. Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, 310058, China

    Xiao Fan, Fangzhou Liu & Aifu Lin

  5. Department of Central Laboratory, the First People’s Hospital of Huzhou, Huzhou, 313000, China

    Xiang Wang

  6. Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China

    Xiang Wang

  7. MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China

    Jinrong Peng

  8. Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China

    Yan Xiong

  9. Breast Center of the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China

    Aifu Lin

  10. International School of Medicine, International Institutes of Medicine, The 4th Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, 322000, China

    Aifu Lin

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  1. Xiao Fan
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  2. Fangzhou Liu
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Correspondence to Fangzhou Liu, Yan Xiong or Aifu Lin.

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Fan, X., Liu, F., Wang, X. et al. LncFASA promotes cancer ferroptosis via modulating PRDX1 phase separation. Sci. China Life Sci. 67, 488–503 (2024). https://doi.org/10.1007/s11427-023-2425-2

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