Dietary Saponin-Mediated Health Promotion: Unraveling the Molecular Mechanism through the PI3K/Akt Signaling Pathway

Dietary saponins, amphiphilic secondary metabolites abundant in legumes, ginseng, and marine organisms, exert various health-promoting benefits primarily through the bidirectional regulation of the PI3K/Akt signaling pathway. This study offers a comprehensive framework unifying saponin-based benefits among metabolic regulation (anti-diabetes, anti-obesity), neuroprotection, acute organ protection, and related clinical outcomes. We elucidate a context-dependent mechanism: while under a degenerative or metabolic stress state, saponins facilitate PI3K/Akt to strengthen glucose uptake (via GLUT4) and cell survival, whereas in an overinflammatory or proliferative state, they dampen hyperactivation to ameliorate tissue injury. Insights of structure-activity relationship and in vivo biotransformation explain their signaling specificity. Moreover, we address the "preclinical-to-clinical gap", focusing on how low oral bioavailability limits direct confirmation of PI3K/Akt modulation in humans, and discuss advanced delivery techniques (e.g., nanocarriers). Via incorporation of the marketed product cases and the proposal of mechanism-driven clinical confirmation, this review provides a roadmap for further development in saponin-based functional food and advanced nutraceuticals.