Gintonin exerts effects via LPAR1/3 and the MEK signaling pathway

Gintonin, a glycolipid protein isolated from Panax ginseng, is a lysophosphatidic acid receptor (LPAR) agonist, which plays a crucial role in cell proliferation, migration, and survival. This study analyzed natural killer group 2 member D (NKG2D) molecules, activation markers for NK cells, using flow cytometry, examined their distribution and NKG2D+ cells via immunohistochemistry, and utilized a YAC-1 tumor to assess cytotoxicity. The relative expression of NK cell–related cytokines and LPARs was detected by reverse transcriptase polymerase chain reaction (RT-PCR) amplification. Inhibitors like LPAR1/3 and MAPK were used to evaluate molecular targets while simultaneously performing transcriptomic analysis of NK cells. Gintonin upregulated expression of NKG2D in peripheral-blood NK cells and splenocytes in a concentration-dependent manner, while NK cell toxicity against tumor cells was enhanced. This promoted the transcription of perforin, IL-2, IFN-γ, TNF-α, and upregulated the LPAR1 gene in NK cells. RT-PCR studies revealed that gintonin activation was inhibited by inhibitors of LPAR1/3 and MAPK-MEK. Transcriptomic analysis indicated gintonin improves NK cell communication and metabolic capacity, positively affecting G protein–coupled receptors and MAPK-MEK signaling pathways. These findings collectively suggest that gintonin targets LPAR1/3 to enhance immune responses in NK cells, suggesting a role for gintonin in immunotherapy.