Saikosaponin C ameliorates renal injury and fibrosis via suppression of the HK2/PKM2/LDHA signaling mediated glycolysis in CKD.

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.