Yang Hong, Chen Yongxin, Wu Guoping, Ren Pengyan, Chen Tingting, Liu Jia, Zhang Bao, Ma Xiao, Jiang Feng, Li Yue, Tao Ling, Shen Xiangchun
Clinical College of Maternal and Child Health Care, Guizhou Medical University, Guiyang, 550003, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability) & School of Pharmaceutical Sciences, No.6 Ankang Avenue, Guizhou Medical University, Guian New District And, Guiyang City, 561113, Guizhou, China; The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education) & State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, No.6 Ankang Avenue, Guizhou Medical University, Guian New District And, Guiyang City, 561113, Guizhou, China.
The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability) & School of Pharmaceutical Sciences, No.6 Ankang Avenue, Guizhou Medical University, Guian New District And, Guiyang City, 561113, Guizhou, China; The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education) & State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, No.6 Ankang Avenue, Guizhou Medical University, Guian New District And, Guiyang City, 561113, Guizhou, China.
Eur J Pharmacol. 2025 Sep 5;1002:177846. doi: 10.1016/j.ejphar.2025.177846. Epub 2025 Jun 14.
Fructus Alpiniae Zerumbet (FAZ), a folk medicinal herb used by the Miao people in Guizhou, China, is rich in 1,8-Cineole - a bioactive monoterpene oxide with antioxidant and neuroprotective properties. However, its therapeutic potential against pancreatic β cells dysfunction, a hallmark of type 2 diabetes mellitus (T2DM), remains unexplored. This study investigated the molecular mechanism by which 1,8-Cineole mitigates hyperglycemia induced β cells ferroptosis. Using high-fat and high-sugar diet/streptozotocin (HFSD/STZ) diabetes mellitus type 2-induced model (DM) and high glucose (HG)-treated β cells model. We demonstrated that 1,8-Cineole ameliorated pancreatic islet structural disorganization and pathological glycogen deposition in diabetic mice. Mechanistically, 1,8-Cineole suppressed lipid peroxidation and iron overload while restoring the expression of ferroptosis markers (GPX4 and COX2). It concurrently resolved autophagy deficiency, as evidenced by upregulated LC3II/I ratio, enhanced Beclin-1 expression, and stabilized p62. Bioinformatic analysis of diabetic pancreatic transcriptomes (GEO dataset GSE25724) linked ferroptosis and PI3K/AKT/mTOR signaling to β cells dysfunction. Cellular thermal shift assay (CETSA) and molecular docking confirmed direct binding of 1,8-Cineole to PI3K with favorable binding energy at the catalytic site. Pharmacological validation using 740-YP (YP, a PI3K agonist) and LY294002 (LY, a PI3K inhibitor) revealed that 1,8-Cineole exerted its anti-ferroptotic effects via PI3K/AKT/mTOR pathway activation. Co-treatment with 740-YP synergistically enhanced β cells protection, whereas LY294002 abrogated 1,8-Cineole's efficacy. Collectively, these findings unveil 1,8-Cineole as a novel PI3K/AKT/mTOR activator that rescues β cells function via coordinated regulation of autophagy and ferroptosis, thereby providing a mechanistic foundation for its therapeutic application in DM.
山柰（FAZ）是中国贵州苗族使用的一种民间草药，富含1,8-桉叶素——一种具有抗氧化和神经保护特性的生物活性单萜氧化物。然而，其对2型糖尿病（T2DM）的标志性特征胰腺β细胞功能障碍的治疗潜力仍未得到探索。本研究调查了1,8-桉叶素减轻高血糖诱导的β细胞铁死亡的分子机制。使用高脂高糖饮食/链脲佐菌素（HFSD/STZ）诱导的2型糖尿病模型（DM）和高糖（HG）处理的β细胞模型。我们证明1,8-桉叶素改善了糖尿病小鼠胰岛结构紊乱和病理性糖原沉积。机制上，1,8-桉叶素抑制脂质过氧化和铁过载，同时恢复铁死亡标志物（GPX4和COX2）的表达。它同时解决了自噬缺陷，这通过上调LC3II/I比率、增强Beclin-1表达和稳定p62得到证明。对糖尿病胰腺转录组（GEO数据集GSE25724）的生物信息学分析将铁死亡和PI3K/AKT/mTOR信号传导与β细胞功能障碍联系起来。细胞热位移分析（CETSA）和分子对接证实1,8-桉叶素在催化位点与PI3K直接结合，结合能良好。使用740-YP（YP，一种PI3K激动剂）和LY294002（LY，一种PI3K抑制剂）进行的药理学验证表明，1,8-桉叶素通过激活PI3K/AKT/mTOR途径发挥其抗铁死亡作用。与740-YP联合治疗协同增强了β细胞保护作用，而LY294002消除了1,8-桉叶素的功效。总的来说，这些发现揭示了1,8-桉叶素是一种新型的PI3K/AKT/mTOR激活剂，它通过协调自噬和铁死亡的调节来挽救β细胞功能，从而为其在糖尿病治疗中的应用提供了机制基础。
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