Piper nigrum L. and its main component piperine ameliorate hyperuricemia and hyperuricemia-related renal inflammation through suppressing the JAK2-STAT3-XDH/SOCS3/TNF-α signalling pathway

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.