Hyperuricemia is a metabolic disease characterized by serum uric acid (UA) levels remaining above normal levels for a long period of time, which has become a huge challenge faced by society. The fruits of P. nigrum L (P. nigrum) as traditional Indian medicine was used to treat various diseases. However, the anti-hyperuricemia effect and mechanism of the ethanol extract of P. nigrum (PE) and its primary component, piperine (PI) still need to be elaborated. In this study, we systematically evaluated the effects of PE and PI on hyperuricemia, as well as their underlying mechanisms in the hyperuricemic mouse and cell models. Our results showed that PE effectively prevented abnormal elevation of UA level, and restored renal function in hyperuricemic mouse model. Transcriptomic and western blot analysis revealed that PE respectively relieved hepatic synthesis of UA and enhanced renal excretion of UA through suppressing the expressions of xanthine dehydrogenase (XDH) and glucose transporter member 9 (GLUT9) in vitro and in vivo. Additionally, PE ameliorated renal inflammation by reducing the expressions of suppressor of cytokine signalling 3 (SOCS3) and TNF-α. Furthermore, the experimental results for PI were consistent with those observed for PE. Mechanistically, the gene overexpression of JAK2, luciferase reporter gene and molecular docking results demonstrated that the anti-hyperuricemia effect of PE was associated with the blocking of the Janus Kinase 2/ Signal transducers and activators of transcription (JAK2/STAT3) signalling transduction, and PI could specifically bound to JAK2. These data suggested that PE could ameliorate hyperuricemia and hyperuricemia-related renal inflammation through suppressing the JAK2-STAT3-XDH/SOCS3/TNF-α signalling pathway, and  the beneficial effects of PE presumably were attributed to PI. In summary, our study suggests that PE may be an effective natural product for improving hyperuricemia by restoring the metabolic balance of UA and suppressing renal inflammation.

Metabolic-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disease globally, with no effective pharmacological treatments available for early-stage cases. Rutin, a bioactive flavonoid from Sophora japonica L., exhibits diverse pharmacological effects, but its multi-pathway mechanisms in improving MAFLD remain unclear. In this study, we employed a high-fat diet (HFD)-induced MAFLD mouse model to investigate the therapeutic effects of rutin supplementation. Rutin supplementation significantly reduced blood lipid and liver lipid levels and alleviated liver injury in MAFLD model mice. Fecal microbiota transplantation experiments revealed that rutin alleviated MAFLD by modulating the gut microbiota composition. Through 16S rRNA sequencing analysis and non-targeted metabolomics analysis of the normal control (NC), HFD and rutin groups, rutin was found to alter key species (Ruminococcus torques) and associated metabolites (e.g., 7-dehydrocholesterol, short-chain fatty acids), suggesting a mechanism involving the gut microbiota. Antibiotic treatment experiments revealed that rutin alleviates MAFLD via the blood entry pathway. Network pharmacology analysis showed that rutin can directly act on targets closely related to MAFLD development, including tumor protein p53, epidermal growth factor receptor, and prostaglandin-endoperoxide synthase 2, as well as key signaling pathways such as PI3K/AKT and MAPK. Transcriptomics analysis of the NC, HFD and rutin groups revealed that rutin may ameliorate MAFLD through PI3K/AKT and MAPK signaling pathways, which might be enhanced by the gut microbiota and blood entry pathways. In conclusion, rutin can treat MAFLD through both the gut microbiota and blood entry pathways, resulting in a synergistic effect. Our study provides a novel strategy for evaluating functional food components and offers a scientific basis for dietary flavonoid-based interventions against MAFLD.