Corynoxine suppresses hepatocellular carcinoma progression by forming the ROS-STAT3 cycle

Hepatocellular carcinoma (HCC) is a type of highly prevalent malignancy characterized by poor prognosis and high rates of recurrence and metastasis. Corynoxine (Cory), a natural alkaloid extracted from Uncaria rhynchophylla, has been identified as an autophagy enhancer. Nevertheless, the biological function of Cory in HCC is yet to be determined. This study aimed to investigate the anti-tumor effects and underlying mechanisms of Cory in HCC using HepG2 and Huh7 cell lines, as well as a xenograft mouse model. Our results demonstrated that Cory significantly suppressed cell growth, migration and invasion, while inducing apoptosis in HCC cells. Mechanistically, Cory promoted intracellular ROS production and inhibited JAK2/STAT3 signaling pathway. The anti-HCC effects of Cory were partially abrogated by the ROS scavenger N-acetyl-L-cysteine (NAC) and the STAT3 activator IL-6, whereas theses effects were potentiated by the STAT3 inhibitor Stattic. Furthermore, NAC pretreatment reversed Cory-mediated STAT3 suppression, IL-6 incubation attenuated Cory-induced ROS production, and Stattic treatment further augmented ROS generation triggered by Cory. These findings suggest the existence of a ROS-STAT3 positive feedback loop activated by Cory in HCC. Consistent with our in vitro observations, in vivo xenograft experiments verified that Cory retarded HCC tumor growth by modulating ROS and STAT3 activity. In summary, this study demonstrates Cory impedes HCC progression via a ROS-STAT3 positive feedback loop, suggesting that Cory may serve as a promising therapeutic candidate for HCC treatment.