{"doi":"10.3390/cancers17183000","title":"Curcumol Targets the VHL/HIF-1α Axis to Suppress Glycolysis-Driven Progression in Colorectal Cancer","abstract":"Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusions: 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.","journal":"Cancers","year":2025,"id":536675,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9605,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1422512,"name":"Zengyaran Yue","orcid":null,"position":1,"is_corresponding":false},{"id":1421997,"name":"Gang Yin","orcid":"0000-0002-0839-242X","position":2,"is_corresponding":false},{"id":435526,"name":"Lifeng Zhu","orcid":"0000-0002-0589-4256","position":3,"is_corresponding":false},{"id":881991,"name":"Wenxia Zhou","orcid":"0000-0002-6175-4821","position":4,"is_corresponding":false},{"id":1422513,"name":"Ruiqian Sun","orcid":null,"position":5,"is_corresponding":false},{"id":1421998,"name":"Tingting Bi","orcid":"0000-0003-2748-1249","position":6,"is_corresponding":false},{"id":1421999,"name":"Lin Zhao","orcid":"0000-0002-2719-3135","position":7,"is_corresponding":false},{"id":1422514,"name":"Yong Bian","orcid":null,"position":8,"is_corresponding":false},{"id":1422000,"name":"Decai Tang","orcid":"0000-0002-4286-2376","position":9,"is_corresponding":false},{"id":419754,"name":"Gang Wang","orcid":"0000-0002-4690-9020","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:52:09.056872Z","pmid":"41008845","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}