2. Academic Validation
  3. 1,8-Cineole ameliorates vascular endothelial senescence in diabetes mellitus by directly targeting and deubiquitinating PPAR-γ in vivo and in vitro

1,8-Cineole ameliorates vascular endothelial senescence in diabetes mellitus by directly targeting and deubiquitinating PPAR-γ in vivo and in vitro

  • J Pharm Anal. 2025 Dec;15(12):101307. doi: 10.1016/j.jpha.2025.101307.
Lingyun Fu 1 2 3,  Shidie Tai 1 2 3,  Jiajia Liao 1 2 3,  Youqi Du 1 2 3,  Guangqiong Zhang 1 2 3,  Die Guo 1 2 3,  Xingmei Chen 1 2 3,  Tian Zheng 1 2 3,  Xiaoxia Hu 1 2 3,  Wenbing Yao 1 2 3,  Ling Tao 1 2 3,  Xueting Wang 1 2 3,  Yini Xu 1 2 3,  Xiangchun Shen 1 2 3
Affiliations

Affiliations

  • 1 The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 561113, China.
  • 2 The Department of Pharmacology of Materia Medica (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, Guizhou Medical University, Guiyang, 561113, China.
  • 3 The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 561113, China.
PMID: 41492461 DOI: 10.1016/j.jpha.2025.101307
Abstract

Vascular endothelial senescence is an important pathophysiological factor in the development and exacerbation of cardiovascular health problems linked to diabetes mellitus (DM). Accumulating evidence confirms that 1,8-cineole has multiple pharmacological properties, including anti-inflammatory, anti-microbial, and antioxidant activities. We investigated whether 1,8-cineole could ameliorate cardiovascular diseases and endothelial dysfunction, as the pharmacological properties and mechanism of diabetic vascular ageing remain unknown. Our results revealed notable senescence biomarkers in both in vivo and in vitro models. Treatment with 1,8-cineole alleviated lipid profiles and vascular senescence in mice with DM. Additionally, bioinformatics analysis suggested that peroxisome proliferator-activated receptor-γ (PPAR-γ) plays a crucial role in DM and ageing. We confirmed the binding capacity PPAR-γ with 1,8-cineole. Accordingly, experiments with the PPAR-γ agonist rosiglitazone, the PPAR-γ inhibitor GW9662, and PPAR-γ siRNA were performed to validate the pharmacological characteristics of 1,8-cineole. Finally, we clarified that 1,8-cineole can directly target PPAR-γ protein, as verified by cellular thermal shift assay, drug affinity responsive target stability, and surface plasmon resonance analyses. Taken together, these results provide the first evidence that 1,8-cineole ameliorates DM-induced vascular endothelial ageing via stabilising PPAR-γ protein by promoting deubiquitination at the Lys-466 site.

Keywords

1,8-Cineole; Peroxisome proliferator-activated receptor-γ; Ubiquitination; Vascular endothelial cell senescence.

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