JI017 induces cell line specific anticancer effects in Hepatocellular Carcinoma by suppressing the STAT3 signaling pathway

Background: Hepatocellular carcinoma (HCC), a predominant cause of cancer-related mortality, is commonly linked to constitutive activation of oncogenic pathways such as STAT3. Continuous STAT3 activation drives tumor progression by enhancing proliferation, survival, and metastatic capability, thus presenting a rational therapeutic target. JI017, an herbal product-based formulation containing Angelica gigas, Aconitum carmichaeli, and Zingiber officinale Roscoe , is rich in bioactive compounds with anti-inflammatory and antioxidant activities. While JI017 has shown anticancer effects in various malignancies, its mechanisms in HCC have not been well characterized. Methods: The impact of JI017 on HCC cells was evaluated using cell viability, colony formation, wound healing, apoptosis, and cell cycle assays. Apoptosis, cell cycle changes, and STAT3 pathway modulation were measured via Western blotting and RT-qPCR. Results: JI017 reduced cell proliferation and migration in both HCC cell lines in a dose-dependent manner. In SNU-387 cells, JI017 strongly induced apoptosis, demonstrated by increased CHOP and DR4 expression and altered apoptosis-related proteins, indicating involvement of both intrinsic and extrinsic pathways. In HepG2 cells, JI017 mainly induced G0/G1 phase arrest, characterized by decreased levels of Cyclin/CDK complexes and increased p21 and p27 expression. Mechanistically, JI017 suppressed STAT3 activation by decreasing Tyr705 phosphorylation, reducing total STAT3 levels, and lowering upstream activators p-JAK2 and p-SRC. This resulted in downregulation of STAT3-regulated genes Cyclin D1, Survivin, and Bcl-2. These anticancer effects were similar or greater than those observed with Stattic, a recognized STAT3 inhibitor. Conclusion: JI017 exerts cell line-specific anticancer effects in HCC through STAT3 pathway suppression, resulting in apoptosis in SNU-387 and cell cycle arrest in HepG2. These results support the potential of JI017 as a STAT3-targeted therapeutic candidate for HCC.