Identification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity

Bei Wang, Arabella H. Wan, Yu Xu, Ruo-Xin Zhang, Ben-Chi Zhao, Xin-Yuan Zhao, Yan-Chuan Shi, Xiaolei Zhang, Yongbo Xue, Yong Luo, Yinyue Deng, G. Gregory Neely, Guohui Wan () and Qiao-Ping Wang ()
Additional contact information
Bei Wang: Shenzhen Campus of Sun Yat-sen University
Arabella H. Wan: Sun Yat-sen University
Yu Xu: Shenzhen Campus of Sun Yat-sen University
Ruo-Xin Zhang: Shenzhen Campus of Sun Yat-sen University
Ben-Chi Zhao: Shenzhen Campus of Sun Yat-sen University
Xin-Yuan Zhao: Shenzhen Campus of Sun Yat-sen University
Yan-Chuan Shi: Garvan Institute of Medical Research
Xiaolei Zhang: Sun Yat-sen University
Yongbo Xue: Shenzhen Campus of Sun Yat-sen University
Yong Luo: Shenzhen Campus of Sun Yat-sen University
Yinyue Deng: Shenzhen Campus of Sun Yat-sen University
G. Gregory Neely: The University of Sydney
Guohui Wan: Sun Yat-sen University
Qiao-Ping Wang: Shenzhen Campus of Sun Yat-sen University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The “death cap”, Amanita phalloides, is the world’s most poisonous mushroom, responsible for 90% of mushroom-related fatalities. The most fatal component of the death cap is α-amanitin. Despite its lethal effect, the exact mechanisms of how α-amanitin poisons humans remain unclear, leading to no specific antidote available for treatment. Here we show that STT3B is required for α-amanitin toxicity and its inhibitor, indocyanine green (ICG), can be used as a specific antidote. By combining a genome-wide CRISPR screen with an in silico drug screening and in vivo functional validation, we discover that N-glycan biosynthesis pathway and its key component, STT3B, play a crucial role in α-amanitin toxicity and that ICG is a STT3B inhibitor. Furthermore, we demonstrate that ICG is effective in blocking the toxic effect of α-amanitin in cells, liver organoids, and male mice, resulting in an overall increase in animal survival. Together, by combining a genome-wide CRISPR screen for α-amanitin toxicity with an in silico drug screen and functional validation in vivo, our study highlights ICG as a STT3B inhibitor against the mushroom toxin.

Date: 2023
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DOI: 10.1038/s41467-023-37714-3

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