Abstract

Ethnopharmacological relevance Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia and metabolic dysregulation, in which pancreatic β-cell dysfunction and local chronic inflammation are key drivers of disease progression. Clinacanthus nutans (Burm. f.) Lindau (CN) is a traditional medicinal plant with anti-inflammatory and antioxidant activities; however, the mechanism underlying its protective effects on pancreatic β-cells in T2DM remains unclear. Aim of the study This study aimed to systematically identify the blood-absorbed constituents of CN and, by integrating multi-omics analyses and in vivo and in vitro experiments, to investigate its pharmacological effects against T2DM and the underlying mechanism by which CN ameliorates islet inflammation and apoptosis via regulation of the chemokine signaling pathways in β-cells. Materials and Methods UHPLC-QTOF-MS was employed to identify the chemical constituents of CN extracts and their prototypes absorbed into the bloodstream. Network pharmacology analysis was performed based on the identified compounds to construct the protein–protein interaction and compound–target networks. Representative binding conformations were subjected to molecular docking and 100-ns molecular dynamics simulations to evaluate binding stability. Transcriptomic sequencing of cellular samples, combined with enrichment analysis, was conducted to elucidate key signaling pathways. The effects of CN were further evaluated in a high-fat diet and streptozotocin-induced T2DM mouse model by assessing glucose metabolism, pancreatic morphology, and markers of inflammation and apoptosis. In MIN6 cells exposed to high-glucose (HG) and palmitic acid (PA) conditions, CN-containing serum (CN-CS) was used to validate its effects on cell viability, insulin secretion, chemokine expression, inflammation, and apoptosis. Results UHPLC-QTOF-MS identified 45 prototype compounds derived from CN in the serum. Both network pharmacology and transc