Saikosaponin D inhibits gastric cancer progression by targeting PKM2-mediated glycolysis and histone lactylation.

Wen-Yen Wang, Fan Zhu, Baomin Du, Liang-duo Jiang, Wei-tao Chen, Guibin Jiang, Yen-Ni Liu, Run Shi, Zhao-Di Fu, Gui-Xing Jin, Jingwen Liu

Phytomedicine

Mar 31, 2026

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Abstract

BACKGROUND: Gastric cancer (GC) represents a prevalent and malignant neoplasm worldwide, characterized by high morbidity and mortality rates. Traditional Chinese medicine offers distinct advantages in the treatment of GC, with Saikosaponin D (SSD), a natural triterpenoid saponin derived from the herb Bupleurum chinense, exhibiting anti-tumor activity in multiple cancer types. Nonetheless, the precise molecular mechanisms underlying SSD's anti-GC effects remain incompletely elucidated. OBJECTIVE: This study aims to explore the proliferation-inhibitory, metastasis-inhibitory, and pro-apoptotic effects of SSD on GC cells, while clarifying its potential mechanism involving PKM2-mediated lactylation and metabolic reprogramming. METHODS: The effects of SSD on cell viability, invasion, migration and apoptosis in BGC-823 and SGC-7901 cells were assessed using assays such as CCK-8, colony formation, transwell, wound healing, flow cytometry, and Western blot. Proteomic sequencing was employed to identify relevant pathways and molecular targets. Furthermore, molecular docking and molecular dynamics (MD) simulations were performed to investigate the interaction between SSD and PKM2. PKM2 overexpression experiments were also carried out to further clarify the underlying mechanisms. An in vivo gastric cancer xenograft mouse model was established to evaluate the antitumor efficacy of SSD. Collectively, these approaches helped highlight SSD's potential as an anticancer agent, particularly in targeting glucose metabolism in gastric cancer. RESULTS: In vitro experiments showed that SSD significantly reduced the viability, proliferation, migration, and invasion of BGC-823 and SGC-7901 cells in a dose-dependent manner, while promoting apoptosis by upregulating cleaved caspase-3/9 expression. In vivo, SSD notably inhibited xenograft tumor growth and decreased Ki-67 expression and pan-lactylation. Mechanistically, SSD downregulated PKM2 expression and suppressed glycolysis-related metabolic processes, thereby reducing pan-lactylation and H3 histone lactylation levels in GC cells. Furthermore, PKM2 overexpression abrogated SSD-induced inhibition of GC cell proliferation and reduction in H3 histone lactylation levels. CONCLUSION: SSD suppresses GC cell growth, migration, and invasion, while promoting apoptosis both in vitro and in vivo. Its anti-tumor mechanism is associated with the suppression of PKM2-mediated glycolysis, and the regulation of global protein lactylation and H3 histone lactylation. These findings highlight SSD's potential as a candidate anticancer agent for GC, particularly by targeting glucose metabolism.