A proposed working model on how the polyphenol-enriched fraction (FMF) from Folium Microcos alleviates APAP-induced liver injury. After administration into the hepatocyte, APAP is first metabolized by cytochrome P4502E1 (CYP2E1) and generates NAPQI, which in turn depletes hepatic GSH and causes mitochondrial dysfunction, resulting in overproduction of ROS. ROS generated from mitochondria and other sources can cause the phosphorylation of JNK, which binds to the mitochondria, leading to enhanced ROS generation. Activated JNK can also phosphorylate transcription factors (e.g., c-Jun and NF-κB) as well as members of the caspase and Bcl2 families to accelerate hepatocyte apoptosis, culminating in severe liver damage. Coadministration of FMF not only alleviated the changes in ROS/MAPKs-mediated apoptotic signaling cascade during APAP challenge but also promoted Nrf2 nuclear translocation and enhanced Nrf2-mediated antioxidant defense system, ultimately leading to reduced oxidative stress and cell death.