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.
背景：缺氧诱导的糖酵解是结直肠癌（CRC）进展的重要标志，并显著促进治疗抵抗。莪术醇是一种从姜黄根茎中提取的天然倍半萜类化合物，已显示出良好的抗肿瘤特性。然而，其在缺氧条件下对代谢重编程的影响尚不明确。 目的：本研究旨在阐明莪术醇通过调控VHL/HIF-1α信号通路抑制糖酵解重编程、阻碍结直肠癌进展的潜力。 方法：在化学诱导的缺氧条件下，用莪术醇处理结直肠癌细胞和原位小鼠模型。通过Seahorse细胞能量代谢分析、Western blot分析、实时定量PCR（qRT-PCR）、免疫组织化学（IHC）和免疫共沉淀（Co-IP）评估代谢变化。通过体外和体内实验对糖酵解和上皮-间质转化（EMT）表型进行功能验证。 结果：莪术醇通过上调VHL表达抑制HIF-1α介导的代谢重编程，从而促进HIF-1α降解。这一效应导致关键糖酵解基因（HK2、LDHA和GLUT1）下调，糖酵解通量和乳酸生成减少，最终抑制结直肠癌细胞增殖和侵袭。莪术醇的抗肿瘤功效在体外和体内模型中得到验证。此外，莪术醇有效逆转了缺氧诱导的上皮-间质转化（EMT）表型，表明其代谢调节作用可能有助于降低转移潜能。 结论：莪术醇通过激活VHL/HIF-1α信号轴抑制糖酵解和结直肠癌进展。这些发现强调了莪术醇作为一种能够逆转肿瘤代谢重编程的天然代谢调节剂的潜力，为结直肠癌治疗提供了一种有前景的治疗策略。
Curcumol Targets the VHL/HIF-1α Axis to Suppress Glycolysis-Driven Progression in Colorectal Cancer
肿瘤(癌症)患者之家