Exploring Antioxidant Synergism Mechanism of 3D Printing Based Shanyao-Fuling-Yiyiren Decoction via Fuzzy Mathematical Method, Network Pharmacology, and In Vitro Experimental Validation.

This study demonstrates the antioxidative stress potential of Shanyao-Fuling-Yiyiren (SFY) decoction-a Chinese polyherbal formulation derived from Si Fang decoction-by establishing a systematic framework that integrates network pharmacology, molecular docking, in vitro synergy assays, cellular experiments, and 3D printing. Despite its long traditional use, the molecular and cellular mechanisms underlying its antioxidative effects remain unclear, and its formulations are based more on empirical methods than on systematic design. To fill this gap, a fuzzy mathematical model was used to select the optimal polyherbal combination. A central composite circumscribed design determined that a Shanyao:Fuling:Yiyiren ratio of 2:2:1 maximized radical scavenging, with a strong correlation (  = 0.9665) between antioxidant activity and the combination index. Furthermore, network pharmacology, molecular docking, and cell-based assays jointly confirm the AKT1/GSK3β/HIF1α pathway plays a crucial role in preventing the antioxidant effects of SFY. Finally, the development of 3D printing SFY-inks with the optimized shape fidelity suggests promising applications for both nutraceuticals and hepatocellular carcinoma diagnosis. Overall, the results prove that 3D printing SFY-based polyherbal formulation with promising antioxidant potential and maximum synergism may indeed be a potential source of preventing oxidant damages in pharmaceutical and food industries.