Context-Dependent Modulation of the TAK1–MAPK Axis by Ginsenoside-Based Formulations Along the NAFLD–HCC Continuum

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. 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. 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. 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.