Kodaka Manami, Matsunaga Yuki, Terada Seiya, Kamei Minami, Suzuki Tsukasa, Yamamoto Yuji, Inoue Jun
Department of Agricultural Chemistry, Faculty of Applied Biosciences, Tokyo University of Agriculture, Tokyo, Japan.
Biosci Biotechnol Biochem. 2025 Apr 22;89(5):704-711. doi: 10.1093/bbb/zbaf012.
Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate various genes involved in cholesterol and fatty acid synthesis, playing a central role in lipid metabolism regulation in vivo. SREBP-1c activity is significantly elevated in the liver under conditions of obesity, fatty liver disease, and type II diabetes, while suppression of SREBP-1c activity has been shown to alleviate these symptoms. Consequently, targeting SREBP-1c activity is considered a potential therapeutic approach for these conditions. In this study, we identified NPD7426 as a compound with inhibitory effects on SREBP activity. Furthermore, we demonstrated that NPD7426 promotes the proteasome-mediated degradation of mature SREBP protein forms. These findings provide new insights into the mechanism of SREBP activity suppression by small-molecule compounds containing NPD7426, suggesting that NPD7426 may be a promising candidate for the development of therapeutic drugs targeting SREBPs.
固醇调节元件结合蛋白（SREBPs）是一类转录因子，可调节参与胆固醇和脂肪酸合成的各种基因，在体内脂质代谢调节中发挥核心作用。在肥胖、脂肪肝疾病和II型糖尿病情况下，肝脏中的SREBP-1c活性显著升高，而抑制SREBP-1c活性已被证明可缓解这些症状。因此，针对SREBP-1c活性进行靶向治疗被认为是治疗这些疾病的一种潜在方法。在本研究中，我们鉴定出NPD7426是一种对SREBP活性具有抑制作用的化合物。此外，我们证明NPD7426可促进蛋白酶体介导的成熟SREBP蛋白形式的降解。这些发现为含NPD7426的小分子化合物抑制SREBP活性的机制提供了新的见解，表明NPD7426可能是开发靶向SREBPs治疗药物的有前途的候选物。
