Chlorogenic acid alleviates chronic restraint stress-induced liver injury potentially via Nrf2-mediated inhibition of ferroptosis and mitochondrial apoptosis

Abstract

Chronic stress primarily induces liver injury through excessive production of reactive oxygen species (ROS), yet the complete underlying mechanisms remain elusive. This study demonstrates that chlorogenic acid (CGA), a natural antioxidant, markedly alleviates chronic restraint stress (CRS)-induced liver injury in rats. Based on histopathological assessment, serum transaminase levels, body weight, and liver coefficient, the optimal CGA dose in this trial was determined to be 100 mg kg⁻¹. CGA treatment significantly reduced liver ROS accumulation, lipid peroxidation, and iron overload, while enhancing glutathione (GSH) levels and regulating iron transport proteins (FPN and TFR1). Mechanistically, CGA may inhibit both ferroptosis and mitochondrial apoptosis via activation of the Nrf2 signaling pathway. These hepatoprotective effects were abolished by the Nrf2 inhibitor brusatol, highlighting the central role of Nrf2 in mediating CGA's antioxidant and cytoprotective actions. This study reveals a novel therapeutic strategy targeting the Nrf2 axis to mitigate oxidative stress and ferroptosis-related liver injury under chronic stress.