Network Pharmacology-Assisted Multi-Omics Analysis of Gut Microbiota–Host Metabolic Remodeling and Hepatic HPD/GSTM3-Associated Redox Responses Following Shanqijing Treatment in STZ-Induced Diabetic Mice

Background/Objectives: Shanqijing (SQJ) is a multibotanical aqueous extract prepared from an equal-ratio blend of Astragali Radix, Dioscoreae Rhizoma, Corni Fructus, Polygonati Rhizoma, and Polygonati Odorati Rhizoma. This study investigated the pharmacological effects and systems-level response pattern of SQJ in streptozotocin-induced diabetic mice. Methods: The study integrated chemical profiling, multi-omics analyses, and network pharmacology-assisted analysis with targeted assessment of hepatic HPD/GSTM3 expression and oxidative stress. Results: UHPLC-Orbitrap MS/MS putatively annotated 250 constituents in SQJ. SQJ lowered fasting blood glucose, improved oral glucose tolerance and serum insulin, reduced inflammatory and hepatic injury indices, and was accompanied by qualitatively improved pancreatic, hepatic, and intestinal histological appearances in representative blinded assessments. Serum metabolomics revealed the partial normalization of aromatic amino acid metabolism, lysophospholipid remodeling, α-linolenic acid metabolism, and polyunsaturated fatty acid-derived oxylipins. SQJ also reshaped the cecal microbiota and partially restored colonic short-chain fatty acids, although the SCFA response was non-monotonic across doses. Integrated metabolite–gene mapping and network pharmacology-assisted compound–target analysis prioritized metabolic and redox-associated host response nodes. Targeted hepatic assessment showed SQJ-responsive normalization of HPD and GSTM3 expression, lower MDA, and recovery of SOD activity and GSH. Conclusions: Collectively, SQJ treatment improved glucose-related and tissue-injury endpoints and was accompanied by coordinated intestinal microbial, circulating metabolic, and hepatic redox responses. These findings are consistent with a distributed systems-level response pattern rather than a single linear gut-to-liver mechanism and provide a basis for further evaluation of SQJ in diabetic metabolic disturbance. The causal contribution of microbial metabolites and the functional requirement for HPD/GSTM3 remain to be established.