Liu Shanshan, Luo An, Que Taolin, Liang Yuxin, Song Yuxin, Liu Tianyi, Li Jing, Li Nan, Zhang Zechen, Liu Yu, Zhang Zecai, Zhou Yulong, Wang Xue, Zhu Zhanbo
College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, China.
College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, 163319, China; Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs, Daqing, 163319, China; Engineering Research Center for Prevention and Control of Cattle Diseases, Heilongjiang Province, Daqing, 163319, China.
Antiviral Res. 2025 Jan;233:106054. doi: 10.1016/j.antiviral.2024.106054. Epub 2024 Dec 9.
For many viruses, controlling the process of infection is largely dependent on the enzymes of the fatty acid synthesis (FAS) pathway. An appealing therapeutic target in antiviral research is fatty acid synthetase (FASN), a crucial enzyme in the FAS pathway. Bovine viral diarrhea, caused by the Bovine viral diarrhea virus (BVDV), is a significant viral infectious disease posing a substantial threat to global animal husbandry. Our study revealed that BVDV infection not only upregulates the expression of FAS-related enzymes in BT cells and the blood, liver, and spleen of mice but also markedly enhances the accumulation of lipid droplets, free fatty acids, and triglycerides. The FAS pathway plays a pivotal role throughout the entire BVDV replication cycle. Additionally, administration of the FASN inhibitor C75 and Acetyl CoA carboxylase-1 (ACC-1) inhibitor TOFA significantly reduced the viral content in both serum and organs of BVDV-infected mice, exhibiting inhibitory effects across diverse viral strains. Intriguingly, We found that RIG-1/TBK1-mediated IFN-I signaling inhibits SREBP-1/FAS and reduces BVDV replication. Conversely, targeting a few essential enzymes of SREBP-1/FAS also activates IFN-I signaling. More importantly, FASN inhibitor led to heightened expression of ISGs in mouse spleens by activating the RIG-1/TBK-1 pathway. These findings highlight that FASN inhibitors inhibit BVDV replication through the activation of the RIG-1/TBK-1 pathway to induce ISGs, and offering a novel therapeutic approach for combating BVDV. Thus, it is crucial to negatively regulate SREBP-1/FAS signaling molecules in order to create novel antiviral drugs that are safe, effective, and broad-spectrum.
对于许多病毒而言，控制感染过程在很大程度上依赖于脂肪酸合成（FAS）途径的酶。抗病毒研究中一个有吸引力的治疗靶点是脂肪酸合成酶（FASN），它是FAS途径中的关键酶。由牛病毒性腹泻病毒（BVDV）引起的牛病毒性腹泻是一种重大的病毒传染病，对全球畜牧业构成重大威胁。我们的研究表明，BVDV感染不仅上调了BT细胞以及小鼠血液、肝脏和脾脏中FAS相关酶的表达，还显著增强了脂滴、游离脂肪酸和甘油三酯的积累。FAS途径在整个BVDV复制周期中起着关键作用。此外，给予FASN抑制剂C75和乙酰辅酶A羧化酶-1（ACC-1）抑制剂TOFA可显著降低BVDV感染小鼠血清和器官中的病毒含量，对多种病毒株均表现出抑制作用。有趣的是，我们发现RIG-1/TBK1介导的I型干扰素（IFN-I）信号传导抑制SREBP-1/FAS并减少BVDV复制。相反，靶向SREBP-1/FAS的一些关键酶也会激活IFN-I信号传导。更重要的是，FASN抑制剂通过激活RIG-1/TBK-1途径导致小鼠脾脏中干扰素刺激基因（ISG）的表达升高。这些发现突出表明，FASN抑制剂通过激活RIG-1/TBK-1途径诱导ISG来抑制BVDV复制，并为对抗BVDV提供了一种新的治疗方法。因此，负向调节SREBP-1/FAS信号分子对于开发安全、有效且广谱的新型抗病毒药物至关重要。
