Liu Yang, Han Dan, Jin Li, Xie Xuena, Li Huibo, Ding Qian, Zhu Yizhun
State Key Laboratory of Quality Research in Chinese Medicine & Laboratory of Drug Discovery from Natural Resources and Industrialization, School of Pharmacy, Macau University of Science and Technology, Macau, China.
Macau University of Science and Technology, Macau, China.
Sci Rep. 2025 Jul 10;15(1):24802. doi: 10.1038/s41598-025-10345-y.
SMYD3 is a chromatin modifier that facilitates the trimethylation of histone 3 lysine 4 (H3K4) to induce diverse biological activities. We have provided a brief demonstration of the anti-aging effect of ZYZ-384, a newly developed inhibitor targeting SMYD3. In order to validate the anti-senescence effect of ZYZ-384, we utilized angiotensin II to induce senescence in two types of human endothelial cells (HMEC-1) and mouse endothelial cells (SVEC4-10), creating cellular models for senescence. Additionally, we employed D-galactose-induced subacute senescence animal models as well as natural senescence animal models. At the cellular level, we assessed proliferation capacity and intracellular markers associated with aging. Aging markers, SASP and differential metabolites were evaluated at an organismal level using animal models. Compared to senescent cells or animals, ZYZ-384 application significantly inhibited levels of aging markers in both senescent cell and senescent animal models while promoting cell proliferation. Furthermore, it suppressed expression of SMYD3 and H3K4me3 along with over expression of HSP 90 and NF-κB. Our study demonstrates that ZYZ-384 is an effective inhibitor targeting SMYD3 which can effectively delay aging.
SMYD3是一种染色质修饰因子，可促进组蛋白3赖氨酸4（H3K4）的三甲基化，从而诱导多种生物学活性。我们已简要证明了ZYZ-384（一种新开发的靶向SMYD3的抑制剂）的抗衰老作用。为了验证ZYZ-384的抗衰老作用，我们利用血管紧张素II在两种类型的人内皮细胞（HMEC-1）和小鼠内皮细胞（SVEC4-10）中诱导衰老，建立衰老细胞模型。此外，我们还采用了D-半乳糖诱导的亚急性衰老动物模型以及自然衰老动物模型。在细胞水平上，我们评估了增殖能力和与衰老相关的细胞内标志物。使用动物模型在机体水平评估衰老标志物、衰老相关分泌表型（SASP）和差异代谢物。与衰老细胞或动物相比，应用ZYZ-384可显著抑制衰老细胞和衰老动物模型中衰老标志物的水平，同时促进细胞增殖。此外，它还抑制了SMYD3和H3K4me3的表达，以及HSP 90和NF-κB的过表达。我们的研究表明，ZYZ-384是一种有效的靶向SMYD3的抑制剂，可有效延缓衰老。
