6-Gingerol ameliorates endothelial injury in hyperlipidemia mice <i>via</i> Nrf2 activation and inflammation modulation

Cardiovascular diseases remain the leading cause of global mortality, with endothelial dysfunction recognized as a critical initiating event. Hyperlipidemia-induced endothelial lipotoxicity triggers oxidative stress and inflammation, thereby accelerating vascular injury. Given the central role of endothelial cells in maintaining vascular homeostasis, they represent a key therapeutic target for mitigating systemic lipotoxicity. However, specific strategies aimed at countering endothelial lipotoxicity remain limited, highlighting an urgent need for novel pharmacological interventions. 6-Gingerol, a primary bioactive constituent of ginger (<i>Zingiber officinale</i>) and related plants, exhibits potent antioxidant, anti-inflammatory, and anticancer properties. Nevertheless, its potential protective effects against hyperlipidemia-induced endothelial injury and the underlying mechanisms remain incompletely understood. In this study, we investigated the protective effects of 6-gingerol and explored its mechanisms of action using both <i>in vivo</i> and <i>in vitro</i> models of endothelial dysfunction. Our results demonstrated that 6-gingerol effectively ameliorates inflammation and oxidative stress associated with endothelial dysfunction induced by hyperlipidemia. Mechanistically, under Nrf2 knockdown conditions, the antioxidant effects of 6-gingerol were abolished. Similarly, inhibition of Erk with U0126 blocked 6-gingerol-mediated nuclear translocation of Nrf2 and its antioxidant activity, underscoring the critical role of the Erk-Nrf2 axis in mediating these effects. Moreover, transcriptomic analysis and pharmacological interventions using a p38 MAPK inhibitor and an NF-κB inhibitor revealed that 6-gingerol suppresses the release of inflammatory mediators, such as IL-6, <i>via</i> the p38 MAPK-NF-κB signaling pathway. In summary, our study provides evidence that 6-gingerol ameliorates lipotoxicity-induced endothelial injury through coordinated modulation of the Erk-Nrf2 and p38-NF-κB signaling pathways, highlighting its potential as a novel preventive candidate for endothelial dysfunction in cardiovascular diseases.