The NLRP3 inflammasome has recently emerged as a viable drug target, and small-molecule inhibitors of this protein complex are being actively tested in preclinical disease models. However, the mechanisms of action for the majority of these compounds remain unclear. Our recent medicinal chemistry campaign led to the discovery of several potent lead NLRP3 inhibitors from a distinct chemical scaffold. Herein, further characterization using biophysical, biochemical, chemical biology, and molecular biology approaches of one of the lead inhibitors revealed direct binding to the NACHT domain of the NLRP3 protein. The studies also suggested potentially multiple binding sites within the NACHT domain that can be targeted by different small-molecule inhibitors. Furthermore, an activity-based probe with high labeling efficacy was developed and can serve as a valuable tool to contribute to ongoing efforts in understanding NLRP3 biology and in developing NLRP3-targeted therapies for various diseases.

2025-11-27·CLINICAL SCIENCE

Loss of LCAT function aggravates metabolic-associated steatohepatitis (MASH) in golden Syrian hamster

Article

作者: Zhao, Mingming ; Lin, Xiao ; Wang, Huan ; Lu, Guotao ; Wang, Yuhui ; Wang, Fuhua ; Xian, Xunde ; Dong, Zhao ; Zhou, Zihao ; Liu, George ; Guo, Xin ; Zheng, Lemin ; Zhang, Yuqing

Lecithin cholesterol acyltransferase (LCAT) plays a pivotal role in acyl-esterifying cholesterol intravascularly, but its function in metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH) has remained uncertain both in murine models and humans for decades, which is largely attributable to the distinct differences in cholesterol metabolism between mice and humans. Previously, we created a novel golden Syrian hamster model deficient in LCAT activity. Herein, we explored the influence of LCAT on the development of MASLD and MASH. A cross-sectional clinical study of LCAT activity and free cholesterol (FC) levels in healthy and MASLD patients was performed. LCAT knockout (LCAT KO) hamsters were used to explore the characteristics of cholesterol homeostasis and MASLD and MASH development. Lipidomics, mRNA-seq, and qPCR were employed to investigate the underlying mechanisms involved. MASLD patients displayed reduced LCAT activity, elevated FC levels, and ratio of FC/TC. Serum FC levels were positively correlated with triglyceride (TG), total cholesterol (TC), and apoB100 levels. In hamsters, LCAT deficiency resulted in increased FC levels and decreased high-density lipoprotein levels. Apolipoprotein profiles revealed increased ApoB100/48 and apoE but decreased apoAI. Increases in serum FC levels were primarily observed in LCAT-deficient hamster. Interestingly, LCAT KO hamsters presented mild TG species deposition in the liver even when fed a chow diet indicated by lipidomics. These increased TG species included TG (16:0/18:1/18:2), TG (16:0/18:1/18:3), and TG (16:0/16:1/18:1). On a high-fat and high-cholesterol diet, LCAT-deficient hamsters developed severe liver ballooning, inflammation, and fibrosis. Using HepG2 cells and primary hepatocytes confirmed that FC increased intracellular lipogenesis and promoted inflammatory response, which was reversed by a NLRP3 inhibitor. In summary, LCAT deficiency in hamsters promotes liver lipid deposition and MASH progression, thus highlighting the therapeutic role of LCAT in MASLD and MASH.

2025-11-01·INTERNATIONAL IMMUNOPHARMACOLOGY

MCC950 attenuates thyroidectomy-induced retching-like behavior by inhibiting NLRP3-mediated IL-1β release

Article

作者: Wang, Xu-Peng ; Zhang, Li-Min ; Ji, Zhi-Sheng ; Liu, Si-Zheng ; Gao, Yue ; Ma, Xiao-Yi ; Li, Wen-Guang ; Li, Lan-Xin

BACKGROUND:

Postoperative nausea and vomiting (PONV) are common complication following surgical procedures, which can significantly impair the quality of patient care, delay discharge, and hinder the resumption of daily activities. In clinical practice, the incidence of PONV after thyroid surgery is approximately 30 %, with a higher prevalence among female patients. Although existing studies have identified various risk factors, treatment methods, and preventive strategies for PONV, research progress in this field has been relatively slow in recent years. Given that rodents lack a functional emetic reflex, precluding direct observation of vomiting, there remains a paucity of suitable animal models for studying PONV. Prior studies have been confined to anatomical and pharmacological investigations, while research on the molecular, cellular, and neural circuit mechanisms of post-thyroidectomy PONV remains scarce. In the existing research, some scientists have defined the behavior of mice opening their mouths as the occurrence of nausea and vomiting in mice. Here, we aim to establish a rodent model of thyroidectomy-induced retching-like behavior (TIRB) in mice to mimic PONV, thereby enabling systematic characterization of its neural and molecular regulatory pathways.

METHODS:

In this study, a mouse model of retching-like behavior was established using thyroidectomy. Using transcriptomics, we explored the up-regulated genes after TIRB, focusing on finding feasible targets for TIRB treatment. Meanwhile, we used immunofluorescence and qPCR to verify the expression of up-regulated genes.

RESULTS:

Our screening revealed that IL-1β, an inflammatory factor associated with NLRP3, was significantly up-regulated after TIRB. In addition, immunofluorescence revealed a significant increase in NLRP3 expression in area postrema, and treatment with MCC950, a specific NLRP3 inhibitor, decreased retching-like behavior incidence in mice.

CONCLUSION:

These results suggest that NLRP3-related molecular pathways may be closely related to TIRB occurrence. NLRP3 could be a novel treatment target of TIRB.

项与 NLRP3 inhibitor(WuXi AppTec) 相关的新闻（医药）

2025-11-03

·BioSpace

Neurocrine Goes to China To Grow Pipeline in up to $881M TransThera Deal

iStock, jozefmicic At the center of the licensing deal is an NLRP3 inhibitor that has shown “encouraging efficacy in acute inflammation models,” according to TransThera, indicating its potential in various metabolic and inflammatory diseases. Neurocrine is joining the gold rush of companies finding assets in China, licensing an NLRP3 inhibitor in a deal with the Nanjing-based TransThera Sciences. Under the terms of the agreement, TransThera will receive an upfront payment along with R&D and sales milestones that could total $881.5 million, the company revealed in a press release Monday. The deal gives Neurocrine rights outside of greater China—including mainland China, Hong Kong, Taiwain and Macao—to TransThera’s portfolio of NLRP3 inhibitors. While the company’s pipeline only lists one candidate, called TT-02332, in that portfolio, TransThera’s release suggests more than one molecule available for licensing. Under the terms of the deal, Neurocrine and TransThera will develop NLRP3 inhibitors for “multiple diseases.” What specific indications could be targeted using the molecule or molecules were not revealed. However, TransThera said, “TT-02332 has shown encouraging efficacy in acute inflammation models, indicating its potential application in various metabolic and inflammatory diseases.” NLRP3 proteins are involved in the inflammasome, an innate cellular response to infection that promotes inflammation. Overactive activation of proteins in the inflammasome pathway are implicated in a number of diseases, including diabetes, atherosclerosis and Alzheimer’s disease. Neurocrine is on the upswing, recently announcing total sales of $790 million for the third quarter of 2025, a 28% year-over-year growth. However, the company is relying almost exclusively on one asset and might be looking to broaden its pipeline. In Q3, $687 million of its Neurocrine’s income came from sales of Ingrezza, its treatment for the movement disorder tardive dyskinesia, as well as chorea associated with Huntington’s disease. Rounding out Neurocrine’s sales was Crenessity, its treatment for congenital adrenal hyperplasia, which reeled in $98 million. Neurocrine made another move to diversify its assets earlier this year, grabbing the depression treatment osavampator from its long-term partner Takeda. That molecule scored a major win in a Phase II trial in 2024, significantly easing symptoms of major depressive disorder in comparison to placebo.

引进/卖出临床2期

100 项与 NLRP3 inhibitor(WuXi AppTec) 相关的药物交易

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