Journal of ethnopharmacology · 2025
Saikosaponin C ameliorates renal injury and fibrosis via suppression of the HK2/PKM2/LDHA signaling mediated glycolysis in CKD.
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Deng Chong, Yang Yang, Bai Qiu-Xiang, Ding Man-Lin, Li Tong, Jia Jian, Tan Rui-Zhi
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Chronic kidney disease (CKD) poses a significant global health burden due to its high morbidity and mortality, with renal fibrosis being a central pathological driver. Saikosaponin C (SSC), a triterpenoid structural analog of the bioactive saikosaponin D (SSD) derived from Bupleurum chinense, exhibits distinct pharmacological profiles. While SSD is recognized for its anti-inflammatory and anti-fibrotic properties, the role of SSC in renal fibrosis remains unexplored.
AIM OF THE STUDY: This study aims to investigate the role of SSC on fibrosis of kidney in CKD, and the underlying mechanism.
MATERIALS AND METHODS: Using unilateral ureteral obstruction (UUO) and adenine (Ade) - induced CKD mouse models as well as TGF-β-induced renal tubular cell model, we assessed the role of SSC on fibrosis, glycolysis, and inflammation. Transcriptomics, molecular docking, and HK2 genetic modification were combined to validate targets.
RESULTS: The results demonstrated that, SSC markedly reduced renal fibrosis (α-SMA and fibronectin) and inflammation (IL-1β, IL-6 and TNF-α) in UUO mice, while suppressing serum lactate accumulation. Mechanistically, hexokinase 2 (HK2) was upregulated in fibrotic kidneys and exhibited strong binding affinity with SSC (binding energy: 9.8 kcal/mol). Silencing HK2 replicated SSC's antifibrotic effects, whereas HK2 overexpression abolished SSC-mediated inhibition of glycolysis and fibrosis. Notably, SSC disrupted the HK2/PKM2/LDHA axis, reducing lactate-driven renal fibrosis.
CONCLUSION: This study identifies HK2 as a critical target of SSC, through which it suppresses glycolytic reprogramming and fibrotic signaling, offering a novel metabolic intervention strategy for CKD.
AIM OF THE STUDY: This study aims to investigate the role of SSC on fibrosis of kidney in CKD, and the underlying mechanism.
MATERIALS AND METHODS: Using unilateral ureteral obstruction (UUO) and adenine (Ade) - induced CKD mouse models as well as TGF-β-induced renal tubular cell model, we assessed the role of SSC on fibrosis, glycolysis, and inflammation. Transcriptomics, molecular docking, and HK2 genetic modification were combined to validate targets.
RESULTS: The results demonstrated that, SSC markedly reduced renal fibrosis (α-SMA and fibronectin) and inflammation (IL-1β, IL-6 and TNF-α) in UUO mice, while suppressing serum lactate accumulation. Mechanistically, hexokinase 2 (HK2) was upregulated in fibrotic kidneys and exhibited strong binding affinity with SSC (binding energy: 9.8 kcal/mol). Silencing HK2 replicated SSC's antifibrotic effects, whereas HK2 overexpression abolished SSC-mediated inhibition of glycolysis and fibrosis. Notably, SSC disrupted the HK2/PKM2/LDHA axis, reducing lactate-driven renal fibrosis.
CONCLUSION: This study identifies HK2 as a critical target of SSC, through which it suppresses glycolytic reprogramming and fibrotic signaling, offering a novel metabolic intervention strategy for CKD.