Urolithin A (UA), an intestinal metabolite of ellagic acid, exhibits significant anti-inflammatory activity. Concurrently, Tumor necrosis factor α (TNF-α) serves as a pivotal inflammatory factor, and induces insulin resistance. This study aims to investigate the ameliorative effect of UA on TNF-α-induced insulin resistance and elucidate its underlying molecular mechanism. Methods and results: Through Western Blot (WB), glucose uptake, and immunocytochemistry (ICC) experiments, it was observed that UA significantly alleviated TNF-α-induced insulin resistance in C2C12 cells. Surface plasmon resonance (SPR) and molecular docking experiments validated the binding of UA to TNF-α with an affinity of 9.626×10^-5M, t which demonstrated UA could directly bind to TNF-α and inhibiting its downstream signaling. These results suggested a potential monoclonal antibody-like mechanism of UA to inhibit TNF-α-induced insulin resistance. Furthermore, we also found the  the substantial inhibitory effect of UA on LPS-induced pro-inflammatory polarization in RAW264.7 cells using WB and ICC experiments. In type 2 diabetes mellitus (T2DM) mouse models, OGTT, ITT, Elisa, WB, and RT-PCR experiments revealed that UA could effectively reduce blood glucose levels and serum concentrations of TNF-α and insulin while enhancing insulin signaling pathway transmission in muscle tissues and upregulating the expression of relevant genes for glycogen synthesis. Additionally, analysis of the intestinal microbiota showed that UA intervention markedly reshaped the composition and structure of the microbial community, reduced the elevated Firmicutes/Bacteroidetes ratio and increased the relative abundance of beneficial genera such as Akkermansia, Dubosiella, and Kurthia, as well as the key species Akkermansia muciniphila, thereby ameliorating HFD/STZ-induced dysbiosis and promoting the functional homeostasis of the intestinal ecosystem in T2DM. Conclusion: UA could directly bind to TNF-α and inhibit its downstream signaling, suggesting a potential monoclonal antibody-like mechanism. UA also exerted inhibitory effects on TNF-α-induced insulin resistance by specifically binding to TNF-α in C2C12 myotubes. We also found that UA could significantly improve insulin resistance, enhanced insulin signaling pathway transmission in muscle tissues, and improved intestinal microbiota dysbiosis.

Epidemiological studies have demonstrated that a range of metabolic diseases, particularly type 2 diabetes and obesity, have reached epidemic proportions. These chronic conditions not only diminish the equality of life for individuals but also impose significant financial burdens on families and healthcare systems. While various therapeutic medications can effectively manage the progression of these diseases, they often come with adverse side effects. In contrast, natural products and their metabolites, such as ellagic acid (EA) and urolithins derived from a variety of plant species, have gained attention for their wide-ranging biological activities, diverse classes, and minimal side effects. Emerging research suggests that EA and urolithins may offer promising therapeutic effects in the treatment of metabolic disorders. This review aims to provide a comprehensive overview of the therapeutic effects and associated signaling pathways of EA and its metabolite urolithins in various metabolic diseases, offering valuable insights for their clinical applications and the potential development of novel food and medicine homologous therapies.