Li Yingjie, Zheng Linlin, Chen Mimi, Li Ruodi, Yu Yansu, Qiao Lu, Liu Jialu, Zhang Xiaopo, Zhang Yong, Zhang Yuxin, Zheng Wei
School of Pharmacy, Harbin University of Commerce, Harbin 150028, China.
Department of Pharmacology, College of Basic Medicine and Life Sciences, Hainan Medical College, Haikou 571199, China.
Molecules. 2025 May 9;30(10):2111. doi: 10.3390/molecules30102111.
Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disorder that imposes a substantial healthcare burden globally. Recent advances highlight the potential of natural products in ameliorating T2DM. In this study, we investigated the therapeutic efficacy of nootkatone (Nok), a natural sesquiterpene ketone, in T2DM and elucidated its underlying mechanisms. In vivo experiments demonstrated that Nok administration markedly improved dysregulated glucose metabolism and ameliorated serum biochemical abnormalities in db/db mice. Leveraging a network pharmacology-based approach, we identified putative molecular targets of Nok. Subsequent in vitro analyses revealed that Nok significantly enhanced glucose consumption in cultured cells. Mechanistically, Nok robustly activated AMP-activated protein kinase (AMPK) while suppressing mitogen-activated protein kinase (MAPK) signaling. Western blot validation further indicated that Nok downregulated the phosphorylation of MAPK1/3 (ERK2/1), attenuating MAPK pathway activation and thereby alleviating metabolic dysfunction-associated fatty liver disease (MAFLD) progression in the diabetic model. Collectively, our findings suggest that Nok exerts anti-diabetic effects via dual modulation of AMPK activation and MAPK inhibition, effectively restoring metabolic homeostasis and mitigating inflammation in T2DM. This study positions Nok as a promising natural compound for therapeutic intervention in T2DM and associated metabolic disorders.
2型糖尿病（T2DM）是一种常见的慢性代谢紊乱疾病，在全球范围内造成了巨大的医疗负担。最近的进展凸显了天然产物在改善T2DM方面的潜力。在本研究中，我们研究了天然倍半萜酮诺卡酮（Nok）对T2DM的治疗效果，并阐明了其潜在机制。体内实验表明，给予Nok可显著改善db/db小鼠失调的葡萄糖代谢，并改善血清生化异常。利用基于网络药理学的方法，我们确定了Nok的推定分子靶点。随后的体外分析表明，Nok显著增强了培养细胞中的葡萄糖消耗。从机制上讲，Nok强烈激活AMP激活的蛋白激酶（AMPK），同时抑制丝裂原激活的蛋白激酶（MAPK）信号传导。蛋白质印迹验证进一步表明，Nok下调了MAPK1/3（ERK2/1）的磷酸化，减弱了MAPK途径的激活，从而减轻了糖尿病模型中与代谢功能障碍相关的脂肪性肝病（MAFLD）的进展。总的来说，我们的研究结果表明，Nok通过双重调节AMPK激活和抑制MAPK发挥抗糖尿病作用，有效恢复代谢稳态并减轻T2DM中的炎症。本研究将Nok定位为一种有前景的天然化合物，可用于T2DM及相关代谢紊乱的治疗干预。
