安徽医科大学吴宝明研究组在研究中取得进展。他们揭示了Kv1.3敲低通过诱导色胺减轻小鼠酒精相关肝损伤。相关论文于2025年6月3日发表在《中国药理学报》杂志上。

在本研究中，研究组研究了Kv1.3通道是否通过调节巨噬细胞功能影响ALD的进展。以雄性小鼠为实验对象，建立小鼠ALD模型。研究人员发现，Kv1.3敲低显著减轻酒精诱导的ALD小鼠肝损伤、脂质沉积和炎症反应。代谢组学分析显示，Kv1.3敲低显著增加了ALD小鼠肝脏中色氨酸代谢物色胺的水平。在EtOH饲喂期的最后5天，分别注射外源三色胺(1, 10, 20 mg·kg⁻¹·d⁻¹, i.p.)。显著减轻乙醇诱导的ALD小鼠肝脏脂肪变性和炎症。在LPS刺激的RAW264.7细胞中，色胺（62.5、125、250μM）剂量依赖性地抑制促炎细胞因子IL-6、IL-1β和TNF-α的分泌。RAW264.7细胞的RNA-seq分析显示，色胺处理显著改变了Toll样受体和NF-κB信号通路。该课题组认为，在ALD小鼠中，Kv1.3负调控色胺水平，通过TLR4/NF-κB信号通路抑制巨噬细胞活化，减轻炎症反应。这些结果为ALD的预防和治疗提供了新的靶点和干预策略。

据悉，酒精相关性肝病（ALD）是指由慢性或急性过量饮酒引起的一系列肝脏疾病。过量饮酒和免疫代谢失调是疾病进展的主要原因。ALD的发病机制尚不清楚，巨噬细胞活性在疾病发展中起关键作用。Kv1.3钾通道对巨噬细胞功能的调控至关重要。

附：英文原文

Title: Kv1.3 knockdown attenuates alcohol-related liver injury in mice through induction of tryptamine

Author: Wang, Hao, Xia, Guo-qing, Ke, Ting, Chen, Xi-xi, Zhen, Wen-jun, Tian, Yuan-yuan, Chen, Shi, Zhang, Cheng, Li, Jun, Zhang, Lei, Wu, De-jun, Wang, Ye-tao, He, Liang, Tian, Wen-fang, Wu, Bao-ming

Issue&Volume: 2025-06-03

Abstract: Alcohol-related liver disease (ALD) refers to a spectrum of liver diseases caused by chronic or acute excessive alcohol consumption. Excess alcohol consumption and dysregulated immunometabolism are the major contributors to the disease progression. The pathogenesis of ALD remains unclear with macrophage activity playing a key role in disease development. Kv1.3 potassium channel is essential for the regulation of macrophage function. In this study, we investigated whether Kv1.3 channels influenced the progression of ALD by modulating macrophage function. A murine model of ALD was established in male mice. We showed that Kv1.3 knockdown significantly attenuated alcohol-induced liver injury, lipid deposition, and inflammatory responses in ALD mice. Metabolomic analysis revealed that Kv1.3 knockdown significantly increased the levels of tryptamine, a tryptophan metabolite, in the liver of ALD mice. During the last 5 days of the EtOH feeding period, injection of exogenous tryptamine (1, 10, 20mg·kg1·d1, i.p.) notably alleviated ethanol-induced liver steatosis and inflammation in ALD mice. In LPS-challenged RAW264.7 cells, tryptamine (62.5, 125, 250μM) dose-dependently suppressed the secretion of pro-inflammatory cytokines IL-6, IL-1β and TNF-α. RNA-seq analysis of RAW264.7 cells revealed that tryptamine treatment significantly altered Toll-like receptor and NF-κB signaling pathways. We conclude that in the ALD mice, Kv1.3 negatively regulates tryptamine levels, which inhibits macrophage activation and reduces the inflammatory responses through the TLR4/NF-κB signaling pathway. Our results offer new targets and intervention strategies for the prevention and treatment of ALD.

DOI: 10.1038/s41401-025-01544-4

Source: https://www.nature.com/articles/s41401-025-01544-4