Identification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity
Bei Wang, Arabella Wan, Yu Xu, Ruo-Xin Zhang, Ben-Chi Zhao, Xinyuan Zhao, Yan‐Chuan Shi, Xiaolei Zhang, Yongbo Xue, Yong Luo, Yinyue Deng, G. Gregory Neely, Guohui Wan, Qiao‐Ping Wang
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.