Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Trigonelline against diabetic nephropathy via targeting MMP9
Jing Wang, Pengjie Zhang, Nan Bao, Peng Du, Bin Duan, Tong Ding · Letters in Drug Design & Discovery · 2025
Background Diabetic nephropathy (DN) is a renal complication arising from diabetes and represents a leading contributor to end-stage renal disease. Current therapeutic strategies for DN are associated with significant limitations. Trigonelline (TRL), a natural alkaloid derived from fenugreek (T rigonella foenum-graecum L.), has shown promise in mitigating diabetes and its associated complications. This study aims to explore the therapeutic potential of TRL in DN and to elucidate the molecular mechanisms underlying its effects. Methods High glucose (HG) was applied to treat HK-2 cells to establish a cell model of DN. Cell viability was detected by Cell Counting Kit-8 (CCK-8) assay. Apoptosis was identified using flow cytometry. The oxidative stress markers, including superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA), were quantified with the corresponding kits. The concentrations of the inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) secreted by the cells were determined via enzyme-linked immunosorbent assay (ELISA). Network pharmacology was employed to forecast drug targets and disease targets. The binding ability between TRL and matrix metalloproteinase-9 (MMP9) was verified by molecular docking technology. Western blotting was applied to evaluate protein expression. A mouse xenograft model was established for the purpose of analysis in vivo . Results TRL ameliorated HG-induced HK-2 cell injury. MMP9 was the target of TRL for the treatment of DN. Suppression of MMP9 mitigated damage to HK-2 cells caused by HG. TRL specifically targeted MMP9 in the therapy for DN. TRL mitigated DN-induced renal damage through modulation of MMP9 expression. TRL attenuated renal injury in DN mice by targeting MMP9. Conclusion The present study revealed the molecular mechanism of TRL targeting MMP9 in the treatment of DN and provided a reference for the wide application of TRL in clinically managing DN.