biostudies-literatureWang GNational Natural Science Foundation of China3000https://www.ebi.ac.uk/biostudies/studies/S-EPMC12468461biostudies-literatureUnknown17(18)<b>Background</b>: Hypoxia-induced glycolysis represents a hallmark of colorectal cancer (CRC) progression and contributes significantly to therapeutic resistance. Curcumol, a natural sesquiterpenoid derived from Curcumae Rhizoma, has demonstrated promising anti-tumor properties. However, its impact on metabolic reprogramming under hypoxic conditions remains largely undefined. <b>Objective</b>: The objective of this study was to elucidate the potential of Curcumol in inhibiting glycolytic reprogramming and impede CRC progression via regulation of the VHL/HIF-1α signaling pathway. <b>Methods</b>: CRC cells and orthotopic mouse models were treated with Curcumol under chemically induced hypoxic conditions. Metabolic alterations were evaluated using Seahorse extracellular flux analysis, Western blot analysis, quantitative real-time PCR (qRT-PCR), immunohistochemistry (IHC) and co-immunoprecipitation (Co-IP). Functional validation of glycolysis and epithelial-mesenchymal transition (EMT) phenotypes was conducted through in vitro and in vivo assays. <b>Results</b>: Curcumol inhibited HIF-1α-mediated metabolic reprogramming by upregulating VHL expression, thereby promoting HIF-1α degradation. This effect led to the downregulation of key glycolytic genes (HK2, LDHA, and GLUT1), decreased glycolytic flux, and lactate production, ultimately suppressing CRC cell proliferation and invasion. The anti-tumor efficacy of Curcumol was validated in both in vitro and in vivo models. Moreover, Curcumol effectively reversed the hypoxia-induced epithelial-mesenchymal transition (EMT) phenotype, suggesting that its metabolic regulatory effects may contribute to reduced metastatic potential. <b>Conclusions</b>: Curcumol suppresses glycolysis and CRC progression by activating the VHL/HIF-1α signaling axis. These findings underscore the potential of Curcumol as a natural metabolic regulator capable of reversing tumor metabolic reprogramming, offering a promising therapeutic strategy for CRC treatment.CancersCurcumol Targets the VHL/HIF-1α Axis to Suppress Glycolysis-Driven Progression in Colorectal Cancer.PMC1246846182474096Yin GZhao LBi TZhu LSun RBian YWang GZhou WTang DYue ZfalseCurcumol Targets the VHL/HIF-1α Axis to Suppress Glycolysis-Driven Progression in Colorectal Cancer.<b>Background</b>: Hypoxia-induced glycolysis represents a hallmark of colorectal cancer (CRC) progression and contributes significantly to therapeutic resistance. Curcumol, a natural sesquiterpenoid derived from Curcumae Rhizoma, has demonstrated promising anti-tumor properties. However, its impact on metabolic reprogramming under hypoxic conditions remains largely undefined. <b>Objective</b>: The objective of this study was to elucidate the potential of Curcumol in inhibiting glycolytic reprogramming and impede CRC progression via regulation of the VHL/HIF-1α signaling pathway. <b>Methods</b>: CRC cells and orthotopic mouse models were treated with Curcumol under chemically induced hypoxic conditions. Metabolic alterations were evaluated using Seahorse extracellular flux analysis, Western blot analysis, quantitative real-time PCR (qRT-PCR), immunohistochemistry (IHC) and co-immunoprecipitation (Co-IP). Functional validation of glycolysis and epithelial-mesenchymal transition (EMT) phenotypes was conducted through in vitro and in vivo assays. <b>Results</b>: Curcumol inhibited HIF-1α-mediated metabolic reprogramming by upregulating VHL expression, thereby promoting HIF-1α degradation. This effect led to the downregulation of key glycolytic genes (HK2, LDHA, and GLUT1), decreased glycolytic flux, and lactate production, ultimately suppressing CRC cell proliferation and invasion. The anti-tumor efficacy of Curcumol was validated in both in vitro and in vivo models. Moreover, Curcumol effectively reversed the hypoxia-induced epithelial-mesenchymal transition (EMT) phenotype, suggesting that its metabolic regulatory effects may contribute to reduced metastatic potential. <b>Conclusions</b>: Curcumol suppresses glycolysis and CRC progression by activating the VHL/HIF-1α signaling axis. These findings underscore the potential of Curcumol as a natural metabolic regulator capable of reversing tumor metabolic reprogramming, offering a promising therapeutic strategy for CRC treatment.2025-01-01T00:00:00Z2025 Sep2026-05-02T03:11:29.909Z2026-05-02T03:07:48.134ZS-EPMC124684614100884510.3390/cancers17183000