Aucubin Inhibits Liver Cancer via HMGB1-mediated Inactivation of the PI3K/AKT/mTOR Signaling Pathway

Introduction: Liver cancer remains one of the most aggressive and lethal malignancies worldwide，and current therapeutic efforts show limited survival benefits. Based on our previous findings that aucubin attenuates liver ischemia-reperfusion injury by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway, this study aimed to elucidate the biological functions and molecular mechanisms of aucubin in liver cancer. Methods: In this study, the role of aucubin in liver cancer was examined using liver cancer cell models and tumor-bearing mouse models. We evaluated whether the anti-tumor effect of aucubin is dependent on HMGB1 and its key signaling pathways. Intellectual property implications related to this small molecule are also explored. Results: Results revealed that aucubin effectively reduced the Epithelial-Mesenchymal Transition (EMT) behavior of liver cancer in nude mice and inhibited the migration and invasion ability of liver cancer cells. The effect of aucubin on migration and proliferation was reversed by HMGB1 overexpression in HepG2 and HCCLM3 cells. Aucubin inhibited the levels of HMGB1, RAGE, p-PI3K, p-AKT, and p-mTOR proteins in mouse tumor tissues and this change was reversed by HMGB1 overexpression. Discussion: We identified that aucubin exerts anti-liver cancer effects. By investigating the regulatory effects of HMGB1 overexpression and AKT agonist SC79 intervention on the HMGB1/ RAGE axis and PI3K/AKT/mTOR pathway, our findings confirmed the core role of the HMGB1/RAGE axis in aucubin’s anti-tumor activity, as well as aucubin’s regulation of liver cancer cell proliferation, migration, and invasion via the PI3K/AKT/mTOR pathway-ultimately mediating its anti-tumor effects. Conclusion: This study indicated that aucubin inhibits the proliferation, invasion, and metastasis of liver cancer by upregulating the HMGB1/RAGE axis and targeting the PI3K/AKT/mTOR signaling pathway. The results of this study highlighted the potential of aucubin as a therapeutic agent for suppressing liver cancer.