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Xin-Zi-Sheng-Wan decoction alleviates hyperuricemia-associated renal injury by inhibiting RIPK1/RIPK3/MLKL-mediated
Jinfang Chen1, Liting Zhu2, Wendi Huang1
1Wenzhou TCM Hospital of Zhejiang Chinese Medical University, Wenzhou, 325000, China.
Ethnopharmacological Relevance:
Xin-Zi-Sheng-Wan Decoction (XZSWD) is a modified formulation derived from the classical prescription Zi-Sheng Pill, which was recorded in Xian Xing Zhai Yi Xue Guang Bi Ji from the Ming Dynasty. Traditionally, this formula is used to eliminate "turbid stagnation" and restore metabolic balance. Contemporary ethnopharmacological evidence indicates that XZSWD can reduce uric acid (UA) levels and ameliorate renal injury, although the molecular mechanism underlying these effects remains incompletely understood.
Aim Of The Study:
The aim of this study was to determine whether XZSWD mitigates hyperuricemia-associated renal injury and to elucidate the underlying mechanisms, with a particular focus on RIPK1/RIPK3/MLKL-mediated necroptosis and oxidative stress in vivo and in vitro.
Methods:
UPLC-QTOF/MS was used to profile XZSWD constituents. A hyperuricemia mouse model was established in C57BL/6J mice using hypoxanthine plus potassium oxonate, followed by XZSWD or febuxostat treatment; serum UA, Cr, and BUN and renal histopathology were assessed, together with Western blot and immunofluorescence. RNA-seq (GSE300922), network pharmacology, and molecular docking were performed to identify key targets and pathways. In vitro, HK-2 cells were treated with tumor necrosis factor-alpha (TNF-α), necroptosis inhibitors, apoptosis inhibitors and XZSWD-medicated serum, and cell viability and Annexin V-FITC/PI flow cytometry were conducted.
Results:
XZSWD lowered serum UA and improved renal function, alleviating tubular injury and fibrosis in hyperuricemic mice. RNA-Seq and network analyses implicated TNF signaling and necroptosis. In HK-2 cells, XZSWD improved viability, reduced reactive oxygen species (ROS) accumulation, and suppressed RIPK1/RIPK3/MLKL phosphorylation, consistent with inhibition of necroptotic cell death.
Conclusions:
XZSWD ameliorates hyperuricemia-associated renal injury by attenuating TNF-α-driven RIPK1/RIPK3/MLKL-mediated necroptosis and oxidative stress.