Nephropathy 1 Formula (N1F) mitigates cisplatin-induced acute kidney injury by inhibiting TAK1-dependent NF-κB...

Nephropathy 1 Formula (N1F) derives from the classical traditional Chinese medicine (TCM) prescription Biejia Jian Wan ("Turtle Carapace Pill"). Rooted in the TCM collateral disease theory, N1F has been clinically used for more than a decade at The First Affiliated Hospital of Wenzhou Medical University to protect renal function. Its therapeutic principles are closely associated with renal microinflammation and fibrosis.

The present study aimed to evaluate the protective effects of N1F against cisplatin-induced acute kidney injury (AKI) and elucidate the underlying molecular mechanisms, with a particular focus on transforming growth factor-β-activated kinase 1 (TAK1)-dependent nuclear factor (NF)-κB signaling and active phytochemical identification.

Cisplatin-challenged C57BL/6 mice were treated with N1F, followed by assessments of renal function, tubular pathology, apoptosis, and inflammation. Mechanistic studies employed HK-2 cells with TAK1 overexpression or inhibition. western blotting, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assays, and immunofluorescence analyses were used to investigate pathway activity. Liquid chromatography-tandem mass spectroscopy profiling integrated with machine learning and molecular docking was used to identify potential TAK1-binding compounds.

N1F significantly improved renal function and alleviated tubular injury in cisplatin-challenged mice, accompanied by the marked suppression of inflammatory responses and apoptosis. Mechanistically, N1F inhibited the phosphorylation of TAK1, IKKβ, and IKBα, thereby preventing NF-κB p65 nuclear translocation. Consistently, the expression of kidney injury markers (Kim-1 and NGAL) and pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, and tumor necrosis factor-α) was significantly reduced. Ginsenoside Rg1, saikosaponin D, saikosaponin B2, ginsenoside F2, and Rg6 were identified as potential TAK1 ligands.

N1F was shown to alleviate cisplatin-induced AKI primarily by inhibiting TAK1-NF-κB signaling. Ginsenosides and saikosaponins are likely to represent key bioactive components contributing to their renoprotective effects.