Senescence of vascular endothelial cells plays a critical role in the initiation and worsening of cardiovascular complications in diabetes mellitus (DM). Extensive research has established that 1, 8-cineole possesses a broad spectrum of pharmacological activities, such as anti-inflammatory, antimicrobial, and antioxidative effects. This study explored the potential of 1, 8-cineole to improve cardiovascular conditions and endothelial impairment, since its effects and mechanisms in diabetic vascular aging have not been fully clarified. Our data showed clear signs of senescence in both animal and cell-based models. 1, 8-Cineole treatment corrected abnormal lipid levels and diminished vascular aging in diabetic mice. Bioinformatics predictions highlighted peroxisome proliferator-activated receptor-γ (PPAR-γ) as a pivotal player in DM and aging. Direct interaction between 1, 8-cineole and PPAR-γ was confirmed. The effects of 1, 8-cineole were further substantiated using the PPAR-γ activator rosiglitazone, the antagonist GW9662, and PPAR-γ-specific siRNA. In addition, direct binding of 1, 8-cineole to PPAR-γ protein was validated through cellular thermal shift assay, drug affinity responsive target stability testing, and surface plasmon resonance experiments. Overall, these data offer the first proof that 1, 8-cineole counters DM-triggered vascular endothelial aging by enhancing PPAR-γ protein stability via deubiquitination at the Lys-466 position.
