Dietary genistein alleviates Aβ-induced toxicity and oxidative stress by modulating the PI3K/Akt/Hsf signaling pathway in Caenorhabditis elegans

Alzheimer’s disease (AD) represents a growing public health challenge, underscoring the urgent need for effective disease interventions. While the soybean-derived isoflavone genistein has significant neuroprotective potential, its precise mechanisms of action remain elusive. This study investigates the neuroprotective profile of genistein against amyloid β (Aβ)–induced toxicity and elucidates its mechanistic pathways. Network pharmacology and molecular docking analyses identified 147 potential targets of genistein, with IGF1R, PIK3R1, and AKT1 emerging as key nodes. Subsequent in vivo validation in Caenorhabditis elegans ( C. elegans ) revealed that genistein supplementation not only prolonged lifespan but also delayed the onset of paralysis ( p < 0.05) and decreased Aβ deposition ( p < 0.05). Furthermore, genistein attenuated ROS accumulation by 66% ( p < 0.01) and boosted antioxidant gene transcription. Crucially, pharmacological suppression of AKT abolished the above effects, demonstrating the functional necessity of the PI3K/AKT/HSF‑1 axis in genistein-mediated neuroprotection. In conclusion, our findings identify a PI3K/AKT/HSF-1-dependent mechanism underlying genistein’s mitigation of Aβ toxicity, supporting the potential of soy-derived polyphenols as mechanistically informed interventions for delaying AD progression.