Triterpenoid saponin variation in cultivated and mountain-cultivated ginseng aqueous extracts is associated with distinct myocardial multi-omics and intestinal microbial-metabolic response patterns.

Cultivated ginseng (CG) and mountain-cultivated ginseng (MCG) are widely used in foods and dietary products; however, it remains unclear whether cultivation-related chemical variation corresponds to different cardiovascular health-related responses. To characterize these composition-function differences, their aqueous extracts were analyzed by widely targeted UPLC-MS/MS and targeted quantification of triterpenoid saponins, and their cardiovascular health-related effects were further evaluated through in vivo, multi-omics, and cell-based analyses. MCG contained higher levels of several triterpenoid saponins, particularly Rh4, Rk1, Rg5, 20(S)-Rg3, and 20(R)-Rg3, and was associated with a more apparent trend toward improvement in cardiac functional and injury-related indices than CG. The two extracts also exhibited distinct myocardial and intestinal-content metabolic profiles. Integrated analyses indicated recurrent enrichment of fluid shear stress and atherosclerosis-related pathways, together with a MEK5/ERK5/MEF2-associated stress-response signature. Rh4 and Rk1, selected as representative MCG-enriched candidate saponins, attenuated oxidative stress, mitochondrial dysfunction, and apoptosis-related changes in H₂O₂-challenged H9C2 cells. Pharmacological inhibition with BIX02189 partially attenuated the Rh4-associated reduction in reactive oxygen species levels and recovery of mitochondrial membrane potential, providing functional support for the involvement of MEK5/ERK5-associated signaling. Collectively, these findings link cultivation-related differences in saponin composition with distinct cardiac and gut-associated responses and provide a composition-function basis for the comparative quality evaluation and potential health-oriented application of ginseng-derived food materials.