The toxicity and side effects of chemotherapeutic drugs remain a crucial obstacle to the clinical treatment of hepatocellular carcinoma (HCC). Identifying combination therapy from Chinese herbs to enhance the sensitivity of tumors to chemotherapeutic drugs is of particular interest. Astragalus polysaccharide (APS), one of the natural active components in Astragalus membranaceus, has been reported to exhibit anti-tumor properties in diverse cancer cell lines. The aim of this study was to determine the effect of APS on Doxorubicin (Dox)-induced apoptosis in HCC and the underlying mechanism. The results showed that APS dose-dependently promoted Dox-induced apoptosis and enhanced endoplasmic reticulum (ER) stress. Additionally, APS decreased the mRNA level and protein stability of O-GlcNAc transferase (OGT), and increased the O-GlcNAcase (OGA) expression. Furthermore, OGT lentiviral transfection or PugNAc (OGA inhibitor) treatment reversed the ER stress and apoptosis induced by the combination of Dox and APS. A xenograft tumor mouse model confirmed that the combination of APS and Dox showed an advantage in inhibiting tumor growth in vivo. These findings suggested that APS promoted Dox-induced apoptosis in HCC cells through reducing the O-GlcNAcylation, which led to the exacerbation of ER stress and activation of apoptotic pathways.

Background: Metabolic reprogramming is a hallmark of cancer, including alterations in the hexosamine biosynthesis pathway (HBP). Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the key regulatory enzyme in the HBP; however, its role in invasive breast carcinoma remains underexplored.Methods: This study utilized integrated data from The Cancer Genome Atlas (TCGA) to assess GFPT1 expression in breast cancer (BRCA) patients. Functional enrichment and mutational landscape analyses were performed, along with chemosensitivity predictions. In vitro experiments were conducted by silencing GFPT1 in malignant breast epithelial cells to evaluate changes in proliferation, migration, and apoptosis.Results: Elevated GFPT1 expression was linked to advanced-stage breast cancer and identified as an independent prognostic marker for overall survival (OS). High GFPT1 levels were associated with increased cytoplasmic translation, activation of oncogenic pathways, and infiltration of M2 macrophages. The GFPT1-High group also showed a higher mutational burden, with frequent TP53 mutations. Chemosensitivity analysis revealed increased IC50 values for chemotherapy drugs in this group. GFPT1 silencing led to reduced cell proliferation and migration, along with enhanced apoptosis.Conclusion: These findings indicate that GFPT1 is a novel prognostic biomarker and a predictive indicator of chemotherapy response in invasive breast carcinoma. GFPT1 influences mRNA translation, cell cycle regulation, and M2 macrophage infiltration, thereby promoting cancer cell proliferation and metastasis.