Polygonati Odorati Rhizoma Extract Ameliorates Obesity and Insulin Resistance Potentially Through Modulation of the TLR4/NLRP3 Signaling Pathway.

BACKGROUND: Polygonati Odorati Rhizoma (Yuzhu) is known to regulate glucose and lipid metabolism and inflammation, but its bioactive components and molecular mechanisms, particularly those involving the TLR4/NLRP3 pathway, remain unexplored. This study integrates chemical profiling, network pharmacology, and experimental validation to investigate whether and how Yuzhu extract ameliorates obesity-associated insulin resistance (IR). METHODS: The chemical constituents of Yuzhu were characterized by UHPLC-Q-TOF-MS/MS. Network pharmacology integrated with GEO dataset analysis was employed to identify potential active compounds, therapeutic targets, and signaling pathways. Molecular docking was performed to evaluate compound-target interactions. A high-fat diet (HFD)-induced obese mouse model and a TNF-α-induced 3T3-L1 adipocyte inflammation model were used for experimental validation. Metabolic parameters, inflammatory cytokines, and TLR4/NLRP3 pathway-related molecules were assessed by biochemical assays, RT-qPCR, Western blot, immunohistochemistry, ELISA, and TUNEL staining. RESULTS: A total of 127 chemical constituents were identified from Yuzhu, of which 67 met the screening criteria for potential bioactivity. Network pharmacology analysis identified 23 overlapping targets and highlighted corchorifatty acid F, 9,10-dihydroxy-12Z-octadecenoic acid, N-trans-feruloyloctopamine, and diosgenin glucoside (DG) as core active components. TLR4 and CCL2 were identified as hub targets, with significant enrichment in the NOD-like receptor signaling pathway. Molecular docking demonstrated favorable binding affinities of the core compounds to TLR4 and NLRP3, with DG exhibiting the strongest binding activity. In vivo, Yuzhu significantly reduced body weight gain, hyperglycemia, dyslipidemia, glucose intolerance, and IR in HFD-fed mice, while suppressing adipose tissue inflammation. Mechanistically, Yuzhu inhibited the expression of TLR4, MyD88, NLRP3, IL-1β, TNF-α, p-p65, p-STAT3, and cleaved caspase-1. In vitro, DG alleviated TNF-α-induced inflammatory responses and apoptosis in adipocytes, whereas recombinant HMGB1 partially reversed these protective effects. CONCLUSION: Yuzhu may alleviate obesity-associated IR through multi-component and multi-target regulation of the TLR4/NLRP3 signaling pathway. DG may represent a key bioactive constituent responsible for these protective effects. These findings provide mechanistic insights and experimental evidence supporting the potential application of Yuzhu in the management of metabolic disorders.