European journal of pharmacology · 2026
Eugenol attenuates ferroptosis, mitochondrial damage, and inflammation in cardiac hypertrophy via the 14-3-3γ/AMPKα2 pathway.
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Zhao Shi-Tao, Qiu Zhi-Cong, Zhou Lian-Fen, Qiu Rong-Bin, Xu Zhi-Qiang, Zeng Rui-Yuan, Lai Song-Qing, Wan Li
Аннотация
BACKGROUND: Chronic stress-induced cardiac hypertrophy is often accompanied by energy metabolism within the mitochondria, iron homeostasis, and inflammation. Eugenol (Eug), as an antioxidant, scavenges reactive oxygen species (ROS) in the body and stabilizes the internal cellular environment. However, the mechanism of this process has not been fully elucidated in existing studies.
METHODS: In this experiment, hypertrophy of H9c2 cells was induced by angiotensin II (Ang Ⅱ), and cardiac hypertrophy was induced by transverse aortic constriction (TAC) in Sprague-Dawley (SD) rats. Subsequently, the impact of Eug pretreatment on cardiac hypertrophy, ferroptosis, mitochondrial injury, and inflammation along with the underlying molecular mechanisms, was investigated using an array of biomarkers.
RESULTS: In vitro model, we demonstrated that both Eug and ferroptosis inhibitor (Ferrostatin-1, Fer-1) pretreatment decreased the expression of cardiac hypertrophy, cell surface area, and inflammatory specific biomarkers (IL6, TNFα), Malondialdehyde (MDA) content, ROS and Fe2+; increased the protein expression of Glutathione Peroxidase 4 (GPX4), and Glutathione /Glutathione Oxidized (GSH/GSSG) ratio. At the same time, Eug reduced the opening of mitochondrial permeability transition pore (mPTP), stabilized mitochondrial morphology (transmission electron microscopy), increased the expression of NDUFB8, UQCRC2, and mitochondrial membrane potential (MMP), ATP production, oxygen consumption rates. These results were abolished by adenoviral downregulation of 14-3-3γ or addition of Compound C (AMPK inhibitor). We also discovered that Eug strengthens the connection between 14-3-3γ and AMPKα2. In vivo model, Eug reduced serum levels of myocardial injury biomarkers and inflammation, improved cardiac function (cardiac ultrasound and HE staining), and attenuated cardiomyocyte hypertrophy and fibrosis (Masson staining and Sirius staining). Furthermore, Eug increased protein expression of 14-3-3γ, GPX4, NDUFB8, and UQCRC2, and the p-AMPKα2/AMPKα2 ratio, decreased MDA, Fe2+ and 4-Hydroxynonenal.
CONCLUSION: Our findings indicate that Eug reduces ferroptosis and inflammation, preserves mitochondrial function, and ultimately mitigates cardiac hypertrophy through the 14-3-3γ/AMPKα2 signaling pathway.
METHODS: In this experiment, hypertrophy of H9c2 cells was induced by angiotensin II (Ang Ⅱ), and cardiac hypertrophy was induced by transverse aortic constriction (TAC) in Sprague-Dawley (SD) rats. Subsequently, the impact of Eug pretreatment on cardiac hypertrophy, ferroptosis, mitochondrial injury, and inflammation along with the underlying molecular mechanisms, was investigated using an array of biomarkers.
RESULTS: In vitro model, we demonstrated that both Eug and ferroptosis inhibitor (Ferrostatin-1, Fer-1) pretreatment decreased the expression of cardiac hypertrophy, cell surface area, and inflammatory specific biomarkers (IL6, TNFα), Malondialdehyde (MDA) content, ROS and Fe2+; increased the protein expression of Glutathione Peroxidase 4 (GPX4), and Glutathione /Glutathione Oxidized (GSH/GSSG) ratio. At the same time, Eug reduced the opening of mitochondrial permeability transition pore (mPTP), stabilized mitochondrial morphology (transmission electron microscopy), increased the expression of NDUFB8, UQCRC2, and mitochondrial membrane potential (MMP), ATP production, oxygen consumption rates. These results were abolished by adenoviral downregulation of 14-3-3γ or addition of Compound C (AMPK inhibitor). We also discovered that Eug strengthens the connection between 14-3-3γ and AMPKα2. In vivo model, Eug reduced serum levels of myocardial injury biomarkers and inflammation, improved cardiac function (cardiac ultrasound and HE staining), and attenuated cardiomyocyte hypertrophy and fibrosis (Masson staining and Sirius staining). Furthermore, Eug increased protein expression of 14-3-3γ, GPX4, NDUFB8, and UQCRC2, and the p-AMPKα2/AMPKα2 ratio, decreased MDA, Fe2+ and 4-Hydroxynonenal.
CONCLUSION: Our findings indicate that Eug reduces ferroptosis and inflammation, preserves mitochondrial function, and ultimately mitigates cardiac hypertrophy through the 14-3-3γ/AMPKα2 signaling pathway.