Multi‐Omics Decoding of <i>Dendrobium huoshanense</i> 's Dual‐Target Mechanism: Modulating Purine and Ether Lipid Metabolism for Type 2 Diabetes Therapy

ABSTRACT As a medicinal‐food homologous species, Dendrobium huoshanense (DH) exhibits promising antidiabetic properties; however, its underlying molecular mechanisms and bioactive components require further systematic investigation. This study investigated the antidiabetic mechanisms of DH through integrated chemical profiling, network pharmacology, and multi‐omics approaches. UPLC‐ESI‐MS/MS characterized 144 constituents, including alkaloids, flavonoids, and bibenzyls. Network pharmacology identified 232 DH‐related targets, with enrichment in T2DM‐associated pathways. In db/db mice, DH treatment significantly reduced fasting blood glucose ( p &lt; 0.01), HbA1c ( p &lt; 0.05), and insulin resistance, alongside ameliorating dyslipidemia and hepatic/renal histopathology. Untargeted proteometabolomic profiling revealed DH‐modulated proteins (18 upregulated and 14 downregulated) and 30 differential metabolites, converging on purine and ether lipid metabolism. Molecular docking highlighted dendrophenol as a key bioactive compound targeting adenosine kinase (ADK) and phospholipase A2 group VII (PLA2G7), critical regulators of insulin resistance and inflammation. Multi‐omics integration demonstrated DH's dual modulation of adenosine metabolism and ether lipid signaling, validated through pathway enrichment and computational simulations. These findings systematically elucidate DH's therapeutic potential, positioning it as a natural multi‐target agent for T2DM management through purinergic and lipid‐inflammatory axis regulation.