Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
CRISPR screen identifies MAP2K3 as a key target for oleuropein to alleviate deoxynivalenol-induced hepatic injury.
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Yang Yaqin, Wu Yue, Xu Xiaoqing, Ihsan Awais, Han Li, Wang Xu
Аннотация
INTRODUCTION: Deoxynivalenol (DON), a widely prevalent mycotoxin in temperate climates, causes significant hepatic injury upon the consumption of contaminated cereals. However, the key targets and mechanisms underlying DON-induced inflammatory hepatic injury remain unclear, thus hindering the development of targeted therapeutics.
OBJECTIVES: This study aimed to identify the key host targets mediating DON-induced inflammatory hepatic injury and its underlying molecular mechanism, as well as to discover potential therapeutic agents for alleviating this damage.
METHODS: We established a J774A.1-CRISPR-Cas9 whole-genome knockout library to screen for host genes essential for DON-induced apoptosis. Structure-based virtual screening was employed to identify MAP2K3 inhibitors, and the mechanism of oleuropein (Ole) action was explored using both in vivo and in vitro models.
RESULTS: CRISPR screening revealed that MAP2K3 is crucial for DON-induced apoptosis. Mechanistically, MAP2K3 mediates inflammatory hepatic injury by activating the p38/p53/caspase-8/caspase-9/caspase-3 pathway. Virtual screening identified Ole as a direct MAP2K3 inhibitor, which binds to key amino acid residues (Lys149, Ser194, Tyr230). Ole effectively inhibited DON-induced hepatic damage in vitro. In the DON-induced murine hepatitis model, Ole demonstrated robust therapeutic effects against DON-induced hepatitis, and its efficacy was superior to that of N-acetylcysteine (NAC).
CONCLUSION: This study demonstrates that MAP2K3 is a key target mediating DON-induced inflammatory hepatic injury and confirms oleuropein (Ole) as a potential therapeutic agent. Together, these findings advance our understanding of the underlying mechanisms and propose a new treatment strategy.
OBJECTIVES: This study aimed to identify the key host targets mediating DON-induced inflammatory hepatic injury and its underlying molecular mechanism, as well as to discover potential therapeutic agents for alleviating this damage.
METHODS: We established a J774A.1-CRISPR-Cas9 whole-genome knockout library to screen for host genes essential for DON-induced apoptosis. Structure-based virtual screening was employed to identify MAP2K3 inhibitors, and the mechanism of oleuropein (Ole) action was explored using both in vivo and in vitro models.
RESULTS: CRISPR screening revealed that MAP2K3 is crucial for DON-induced apoptosis. Mechanistically, MAP2K3 mediates inflammatory hepatic injury by activating the p38/p53/caspase-8/caspase-9/caspase-3 pathway. Virtual screening identified Ole as a direct MAP2K3 inhibitor, which binds to key amino acid residues (Lys149, Ser194, Tyr230). Ole effectively inhibited DON-induced hepatic damage in vitro. In the DON-induced murine hepatitis model, Ole demonstrated robust therapeutic effects against DON-induced hepatitis, and its efficacy was superior to that of N-acetylcysteine (NAC).
CONCLUSION: This study demonstrates that MAP2K3 is a key target mediating DON-induced inflammatory hepatic injury and confirms oleuropein (Ole) as a potential therapeutic agent. Together, these findings advance our understanding of the underlying mechanisms and propose a new treatment strategy.