Context-dependent modulation of the TAK1-MAPK axis by ginsenoside-based formulations along the NAFLD-HCC continuum.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a dynamic metabolic liver disorder that can progress to hepatocellular carcinoma (HCC). Stress-responsive signaling pathways, particularly the transforming growth factor-β-activated kinase 1 (TAK1)-mitogen-activated protein kinase (MAPK) axis, play context-dependent roles in hepatocyte survival, disease adaptation, and tumorigenesis. METHODS: Two ginseng-derived formulations with distinct biological properties were investigated: a non-cytotoxic Rg5/Rk1-triterpene complex and a cytotoxic Rg3/paclitaxel liposomal formulation. Cytotoxicity and signaling responses were evaluated in HepG2 hepatocellular carcinoma cells, MKN1 gastric cancer cells, and HEK293T cells. Cell viability was assessed using MTT assays. TAK1-MAPK signaling was analyzed by Western blotting and overexpression experiments, and cellular thermal shift assays were performed to examine target engagement. RESULTS: Rg5/Rk1-triterpene enhanced TAK1 autophosphorylation and activated downstream MAPK signaling without inducing cytotoxicity, consistent with an adaptive stress-response profile. This modulation was accompanied by selective upregulation of the RNA editing enzyme ADAR2, while global translational regulators such as eIF6 remained unchanged. In contrast, Rg3/paclitaxel liposomes induced cytotoxic stress and suppressed MEK-ERK signaling in hepatic and gastric cancer cells, supporting a pro-apoptotic mechanism. These opposing effects demonstrate formulation-dependent regulation of the TAK1-MAPK signaling axis. CONCLUSION: These findings suggest that ginseng-derived formulations differentially modulate the TAK1-MAPK pathway and may represent a context-dependent signaling framework relevant to different stages of liver disease progression.