Potential roles of plant metabolites and Traditional Chinese Medicine formulas in regulating glycolysis-OXPHOS plasticity in gastric precancerous lesions and gastric cancer: a critical appraisal of the evidence.

内容摘要

The Warburg effect in tumor cells is characterized by increased glucose uptake, enhanced glycolytic flux, and the conversion of pyruvate to lactate for energy generation, rather than its utilization in oxidative phosphorylation (OXPHOS), even under aerobic conditions. This metabolic reprogramming, coupled with OXPHOS dysfunction, is closely correlated with the initiation, invasion, metastasis, chemoresistance, and poor prognosis of gastric precancerous lesions (GPL) and gastric cancer (GC). Therefore, modulating the glycolytic and OXPHOS-related signaling pathways intertwined with microbial regulation presents a novel therapeutic strategy for GPL and GC treatment. Plant metabolites and TCM formulas exhibit potential advantages in regulating GPL and GC metabolism because they may modulate multiple steps of glycolysis and influence OXPHOS-related abnormalities in preclinical models, thereby contributing to restoration of mitochondrial functional homeostasis. However, these effects should generally be interpreted as metabolic modulation observed in experimental systems rather than definitive evidence of direct molecular targeting. We found that botanical drugs and plant metabolites were frequently associated with changes in GPL and GC metabolism through signaling networks involving phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), Hippo, hypoxia-inducible factor (HIF)-1α, c-Myc, and non-coding RNAs. These regulatory effects were accompanied by modulation of glycolysis- and OXPHOS-related enzymes and markers, and were often linked to reduced proliferation, invasion, metastasis, and chemoresistance in GPL and GC models. Nevertheless, for many pathways, the available evidence remains correlative rather than demonstrating direct target engagement. Plant metabolites and TCM formulas exhibit distinct advantages in regulating GPL and GC metabolism, as they can modulate multiple steps of glycolysis and modulate dysregulated OXPHOS pathways in GPL and GC cells to restore mitochondrial functional homeostasis. This process involves the transient modulation of specific OXPHOS complexes to correct abnormal mitochondrial energy metabolism and achieve the net restoration of ATP balance. Leveraging plant metabolites and TCM formulas to modulate these metabolic processes thus represents a promising therapeutic approach for GPL and GC management. This review summarized the research progress on the intervention effects of botanical drugs and plant metabolites on GPL and GC metabolic reprogramming, based on relevant studies retrieved from Chinese databases (CNKI, Wanfang, VIP) and English databases (PubMed, Web of Science, Embase) from the establishment of each database to October 2025, using a combination of subject terms and free words (including "gastric cancer, gastric precancerous lesions, glycolysis, oxidative phosphorylation, OXPHOS, botanical drug, plant metabolite, TCM formula" and their corresponding Chinese translations) restricted to the title, abstract, and keyword fields. We found that botanical drugs and plant metabolites primarily regulated GPL and GC metabolism by modulating key signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), Hippo, hypoxia-inducible factor (HIF)-1α, c-Myc, and non-coding RNAs. These regulatory effects further modulated the activity of enzymes associated with glycolysis and OXPHOS, ultimately inhibiting the proliferation, invasion, and metastasis of GPL and GC cells while enhancing their chemosensitivity. Elucidating the regulatory mechanisms of botanical drugs and plant metabolites on GPL and GC metabolic reprogramming, including glycolysis and OXPHOS, not only helped clarify the therapeutic basis of plant metabolites and TCM formulas against GPL and GC but also provided a theoretical foundation for the development of novel anti-GC strategies.