Cinnamaldehyde alleviates hepatic steatosis correlating with its electrophilic capability

Cinnamaldehyde (CA) is the key component of the essential oil derived from cinnamon bark and recommended as a health factor in foods for the prevention and intervention of metabolic disorders. This research aims to reveal the association between the difference in the electrophilic abilities of functional groups in CA and 3-phenylpropionaldehyde (PA), and their regulation of lipid peroxidation as well as energy metabolism in free fatty acids (FFAs) overloaded HepG2 cells. CA treatment reduced lipid accumulation and synthesis-related factors, increased levels of factors associated with fatty acid β-oxidation, decreased reactive oxygen species (ROS) content, and restored mitochondrial function and was superior to PA. Moreover, CA treatment increased nuclear Nrf2 protein levels and regulated the nuclear/cytoplasmic Nrf2 ratio, which suggested that CA effectively upregulated the Nrf2 signaling pathway. Furthermore, molecular docking showed that CA possessed an electrophilic index of 2.45 covalently bound to Nrf2-associated Keap1 protein with an affinity of −3.6 kcal/mol, which was much stronger than PA, and HPLC-MS/MS analysis further confirmed that CA covalently modified Cys151 on Keap1 protein. In conclusion, CA has the capacity to attenuate hepatic steatosis and cellular oxidative response via Nrf2 signaling pathway, which is closely related to its strong electrophilic ability.