- Non-cytotoxic Rg5/Rk1 complex enhances TAK1 autophosphorylation and activates downstream MAPK, eliciting adaptive stress response and selective ADAR2 upregulation.
- Cytotoxic Rg3/paclitaxel liposomes induce cell death and suppress MEK-ERK signalling in hepatic and gastric cancer cells, consistent with pro-apoptotic mechanism.
- Formulation-dependent modulation of the TAK1-MAPK axis provides a context-dependent signalling framework relevant to NAFLD progression and HCC development.
J Ginseng Res. 2026 Sep;50(5):101024. doi: 10.1016/j.jgr.2026.101024. Epub 2026 Mar 25.
ABSTRACT
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.
PMID:42718885 | PMC:PMC13554437 | DOI:10.1016/j.jgr.2026.101024
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