Xue Qingkai, Zhou Xiangyu, Wang Yuyan, Liu Yiyun, Li Xiaojing, Xiong Chunrong, Liu Xinjian, Huang Yuzheng
National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, China.
Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China.
PLoS Negl Trop Dis. 2025 Feb 11;19(2):e0012854. doi: 10.1371/journal.pntd.0012854. eCollection 2025 Feb.
Schistosomiasis is the second most important parasitic disease worldwide. Schistosomiasis japonica is a unique species endemic to southern China, and schistosomiasis is characterized by severe liver injury, inflammation, liver granuloma, and subsequent liver fibrosis. However, the pathological mechanism of this disease remains unclear. Mass spectrometry imaging (MSI) is a versatile technique that integrates the molecular specificity of mass spectrometry (MS) with spatial imaging information, which could provide an accurate method for observing disease progression. In this study, we used an air flow-assisted desorption electrospray ionization (AFADESI-MSI) platform to detect a wide range of metabolites and visualize their distribution in the liver tissue of mice infected with Schistosoma japonicum. In the negative ion mode analysis, 21 and 25 different metabolites were detected in the early and chronic stages of infection, respectively. Thirteen characteristic metabolites and 3 metabolic pathways related to disease development may be involved in the chronicity of schistosomiasis. There were more than 32 and 40 region-specific changes in the abundance of a wide range of metabolites (including carbohydrates, amino acids, nucleotides, and fatty acids) in the livers of mice at two different infection times, which also revealed the heterogeneous metabolic characteristics of the liver egg granulomas of S. japonicum. In a chronic infection model with S. japonicum, oral treatment with praziquantel significantly alleviated most metabolic disorders, including fatty acid and pyrimidine metabolism. Surprisingly, Upase1, a key enzyme in uridine metabolism, was significantly upregulated 6 weeks after infection, and liver uridine levels were negatively correlated with the abundance of multiple lipid-associated metabolites. Further studies revealed that in vitro uridine supplementation inhibited the activation of LX-2 cells, restored the homeostasis of fatty acid metabolism through the peroxisome proliferator-activated receptor γ (PPARγ) pathway, and played an antifibrotic role. Our findings provide new insights into the molecular mechanisms of S. japonicum-induced liver fibrosis and the potential of targeting uridine metabolism in disease therapy.
血吸虫病是全球第二重要的寄生虫病。日本血吸虫病是中国南方特有的一种血吸虫病，其特征是严重的肝损伤、炎症、肝肉芽肿及随后的肝纤维化。然而，该病的病理机制仍不清楚。质谱成像（MSI）是一种多功能技术，它将质谱（MS）的分子特异性与空间成像信息相结合，可为观察疾病进展提供一种准确的方法。在本研究中，我们使用气流辅助解吸电喷雾电离（AFADESI-MSI）平台检测了多种代谢物，并可视化它们在感染日本血吸虫的小鼠肝脏组织中的分布。在负离子模式分析中，分别在感染的早期和慢性期检测到21种和25种不同的代谢物。13种特征性代谢物和3条与疾病发展相关的代谢途径可能与血吸虫病的慢性化有关。在两个不同感染时间点，小鼠肝脏中多种代谢物（包括碳水化合物、氨基酸、核苷酸和脂肪酸）丰度存在32个以上和40个以上区域特异性变化，这也揭示了日本血吸虫肝卵肉芽肿的异质性代谢特征。在日本血吸虫慢性感染模型中，吡喹酮口服治疗显著缓解了包括脂肪酸和嘧啶代谢在内的大多数代谢紊乱。令人惊讶的是，尿苷代谢中的关键酶Upase1在感染后6周显著上调，肝脏尿苷水平与多种脂质相关代谢物的丰度呈负相关。进一步研究表明，体外补充尿苷可抑制LX-2细胞的激活，通过过氧化物酶体增殖物激活受体γ（PPARγ）途径恢复脂肪酸代谢的稳态，并发挥抗纤维化作用。我们的研究结果为日本血吸虫诱导肝纤维化的分子机制以及疾病治疗中靶向尿苷代谢的潜力提供了新的见解。
