Triptolide Inhibits Renal Fibrosis Through Promotion of PGC1α/PCK1-mediated Renal Gluconeogenesis

BACKGROUND: Recent studies have identified impaired renal gluconeogenesis as a hallmark of chronic kidney disease. Triptolide is a natural compound widely used in China for the treatment of renal diseases. This study investigated whether triptolide mitigates renal fibrosis by promoting renal gluconeogenesis. METHODS: model to investigate renal fibrosis. Metabolomics, western blotting, immunohistochemistry (IHC), and metabolic assays were performed to investigate the underlying mechanisms. RESULTS: Triptolide reduced the expression of several fibrotic markers in the kidneys of UUO mice. Metabolomic analysis revealed enhanced renal gluconeogenesis following treatment with triptolide, which was confirmed by analyzing gluconeogenic enzyme expression and lactate concentration in UUO kidneys. The pro-gluconeogenic effect of triptolide was further confirmed in TGF-β-stimulated HK2 cells. Inhibition of phosphoenolpyruvate carboxykinase 1 (PCK1) reversed the anti-fibrotic and pro-gluconeogenic effects of triptolide in TGF-β-stimulated HK2 cells. We further demonstrated that peroxisome proliferator-activated receptor-gamma co-activator 1 alpha (PGC1α) expression was downregulated in TGF-β-stimulated HK2 cells and UUO kidneys, and that triptolide reversed this downregulation. Moreover, the PGC1α inhibitor reversed the effect of triptolide on PCK1 expression and glucose metabolism. Finally, IHC analysis revealed that triptolide inhibited histone lactylation in UUO kidneys, which was associated with a decreased production of inflammatory factors and reduced macrophage infiltration. CONCLUSIONS: Triptolide may inhibit renal fibrosis by increasing the PGC1α/PCK1 axis, thereby promoting renal gluconeogenesis. This cascade may reduce histone lactylation and renal inflammation, providing a mechanistic pathway for its anti-fibrotic effect.