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.