Integrative analysis of chemical profiling proposes sesamin as a computationally prioritized, putatively annotated candidate in SQ–DS–HQ for diabetic neuropathy

Abstract

Diabetic peripheral neuropathy (DPN) is a common diabetes complication with complex inflammatory, hypoxic and neurodegenerative features. Sanqi–Danshen–Huangqi (SQ–DS–HQ) is a traditional Chinese herbal formula used for diabetes-related complications, yet its chemical basis and mechanisms in DPN remain unclear. We combined UHPLC–MS/MS chemical profiling, target prediction, transcriptomic analysis, machine learning, network analysis, and molecular simulations to explore multi-target mechanisms of SQ–DS–HQ against DPN and prioritize candidates. A total of 368 metabolites were tentatively annotated (Level 2 confidence), and 25 were retained as putative active constituents. Integration of drug-disease targets, protein–protein interaction networks, and transcriptomic screening identified eight core targets: IL6, CASP3, STAT3, BCL2, AKT1, JAK2, MTOR and HIF1A. AGE-RAGE, HIF-1 and JAK-STAT signaling were the main enriched pathways. Immune infiltration analysis associated AKT1, JAK2 and HIF1A with macrophages, mast cells and M1 macrophages, respectively. A compound tentatively annotated as sesamin exhibited broad in silico docking activity and relatively stable simulated binding modes with AKT1, BCL2 and JAK2. These findings generate a testable hypothesis that SQ–DS–HQ may coordinately modulate inflammatory, hypoxic and apoptotic networks. The computationally prioritized candidate sesamin requires authentic standard confirmation before biological testing.