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Inhibition of Macrophage Pyroptosis─A New Therapeutic Strategy to Alleviate T-2 Toxin-Induced Subacute Liver Injury
Xiaoqing Xu1,2, Yue Wu3, Yongxia Zhao1,2
1National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan , Hubei 430070, China.
Abstract:
Multiple compounds are related to the development of liver injury, such as toxins, drugs, and environmental pollutants. Although there are reports that the T-2 toxin can cause liver injury, its toxic mechanism remains unclear, which further impedes the development of effective antidotes. In this study, CRISPR-Cas9 genome-wide screening technology was used to identify transformation-related protein 53 inducible nuclear protein 1 (trp53inp1) as a toxic target of the T-2 toxin. Mechanism studies have shown that the T-2 toxin induced pyroptosis of macrophages (J774A.1 cells) by activating the trp53inp1/NF-κB/NLRP3/GSDMD-N pathway, leading to a subacute liver injury. Also, the new drug berberine (BER) identified through virtual screening significantly alleviated the subacute liver injury by competitively binding trp53inp1 via His224; the effect was better than those of the positive control drugs N-acetylcysteine (NAC) and disulfiram (DSF). In summary, the above results indicate that trp53inp1 is a key target for T-2 toxin to induce subacute liver injury and that inhibiting macrophage pyroptosis is a new method for treating liver injury. In addition, this study provides a new method and strategy for the discovery of key disease targets and the search for effective drugs.
Insights
T-2 toxin causes liver injury by activating the transformation-related protein 53 inducible nuclear protein 1 (trp53inp1) pathway, leading to macrophage pyroptosis. Berberine drug effectively alleviates this injury by targeting trp53inp1.
Area of Science:
- Toxicology
- Molecular Biology
- Drug Discovery
Background:
- Liver injury can result from toxins, drugs, and environmental pollutants.
- The precise toxic mechanism of T-2 toxin-induced liver injury is not fully understood.
- Identifying molecular targets is crucial for developing effective antidotes.
Purpose of the Study:
- To elucidate the toxic mechanism of T-2 toxin in liver injury.
- To identify the specific molecular target of T-2 toxin.
- To discover potential therapeutic agents for T-2 toxin-induced liver injury.
Main Methods:
- CRISPR-Cas9 genome-wide screening was employed to identify T-2 toxin targets.
- Mechanism studies investigated the role of transformation-related protein 53 inducible nuclear protein 1 (trp53inp1) in T-2 toxin-induced pyroptosis.
- Virtual screening identified berberine (BER) as a potential therapeutic agent, with its binding mechanism elucidated through molecular interactions.
Main Results:
- CRISPR-Cas9 screening identified trp53inp1 as a key toxic target of T-2 toxin.
- T-2 toxin induces macrophage pyroptosis via the trp53inp1/NF-κB/NLRP3/GSDMD-N pathway, causing subacute liver injury.
- Berberine significantly alleviated liver injury by competitively binding trp53inp1 at His224, outperforming NAC and DSF.
Conclusions:
- trp53inp1 is a critical mediator of T-2 toxin-induced subacute liver injury.
- Inhibiting macrophage pyroptosis presents a novel therapeutic strategy for liver injury.
- This study offers a framework for identifying disease targets and discovering drugs.
