Chicoric acid targets PYGL to normalize glycogenolysis-driven glycolysis to suppress non-small cell lung cancer

BACKGROUND: Chicoric acid (CA), a bioactive natural compound found in Chicory and Echinacea purpurea, exhibits antiinflammatory, antioxidant, and apoptosis-inducing properties. However, its therapeutic potential and underlying mechanisms in non-small cell lung cancer (NSCLC) remain unclear. METHODS: We utilized bioinformatics analysis to identify potential hub genes targeted by CA. The clinical relevance of glycogen phosphorylase liver form (PYGL) was assessed via immunohistochemistry in NSCLC tissues. Functional assays, including Cell Counting Kit-8, flow cytometry, and xenograft models, were employed to evaluate the impact of PYGL on tumor growth. Glycogen metabolism and glycolytic flux were monitored using PAS staining and Seahorse assays. Direct binding between CA and PYGL was confirmed through virtual screening, molecular docking, cellular thermal shift assay, and surface plasmon resonance. Binding specificity was further validated using site-directed mutagenesis. RESULTS: Here, we demonstrate that CA restores glucose metabolic homeostasis and inhibits the proliferation of NSCLC cells. We identified PYGL as a key driver of NSCLC, where its upregulation enhances glycogenolysis to fuel glycolytic flux and promote tumor growth. Mechanistically, CA allosterically inhibits PYGL by binding to specific residues (Glu162, Arg247, Glu273) and inducing conformational changes, thereby suppressing glycogenolysis and reducing glycolysis. Furthermore, CA disrupts the interaction between PYGL and lactate dehydrogenase A (LDHA), accelerating the proteasomal degradation of LDHA and further reshaping glucose metabolic homeostasis. CONCLUSIONS: Our findings highlight PYGL as a metabolic vulnerability in NSCLC and establish CA as a promising lead compound that targets the PYGL-LDHA axis to reprogram glucose metabolism and inhibit tumor growth.