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

  • J Ethnopharmacol. 2025 Sep 25;353(Pt A):120283. doi: 10.1016/j.jep.2025.120283.
Chong Deng  1 ,  Yang Yang  2 ,  Qiu-Xiang Bai  3 ,  Man-Lin Ding  4 ,  Tong Li  3 ,  Jian Jia  5 ,  Rui-Zhi Tan  6
Affiliations
  • 1. Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China; Clinical Laboratory, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China.
  • 2. Experimental Animal Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 3. Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China.
  • 4. Clinical Laboratory, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China.
  • 5. Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China. Electronic address: [email protected].
  • 6. Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China. Electronic address: [email protected].
PMID: 40659145 DOI: 10.1016/j.jep.2025.120283
Abstract

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.

Keywords
Chronic kidney disease; Glycolysis; HK2; Lactate; Saikosaponin C.
Products