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<p>Gastric cancer (GC) is a very aggressive cancer with a high potential for metastasis. A naturally occurring flavonoid, luteolin (Lut) has metabolic regulation and anti-cancer properties. This work investigates whether Lut modulates glucose metabolism and targets AKR1B1 to prevent the epithelial-mesenchymal transition (EMT) in GC. Lut was used to treat human GC cell lines that were grown in both normal and high-glucose environments. Western blotting and qPCR were used to assess the expression levels of EMT markers and AKR1B1. The CCK-8 assay, the scratch assay, and the Transwell assay were used to measure cell movement, invasion, and proliferation, respectively. Metabolic flux analysis was used to measure fructose and lactate generation in order to assess glycolytic activity. We carried out AKR1B1 overexpression and knockdown experiments to elucidate the functional involvement of AKR1B1 in the action of Lut. In order to fully assess the anticancer effects of Lut and its underlying mechanisms, a high-glucose paradigm in nude mice was developed for in vivo validation. AKR1B1 expression was markedly elevated in GC cells under high-glucose circumstances, and this was accompanied by increased glycolytic activity. At the same time, the cells showed signs of EMT, including enhanced migratory and invasion capacities. Subsequent research showed that Lut therapy substantially alleviated anomalies in glucose metabolism by drastically suppressing AKR1B1 expression, downregulating important glycolytic enzymes, and reducing the generation of fructose and lactate. Additionally, by boosting E-cadherin expression, lowering vimentin and N-cadherin levels, and preventing cell migration and invasion, luteolin dramatically corrected high-glucose-induced EMT. The inhibitory effects of luteolin on glycolysis and EMT were largely offset by AKR1B1 overexpression, according to functional experiments; on the other hand, inhibition of AKR1B1 considerably reduces AKT pathway activation, which suppresses the malignant phenotype of gastric cancer cells. Together, these findings show how important AKR1B1 is to this regulatory axis. According to these results, luteolin inhibits high-glucose-induced metabolic reprogramming and EMT in gastric cancer cells via acting on AKR1B1, which lowers the cells’ capacity for metastasis. Lut may reduce the metabolic dysregulation brought on by hyperglycemia by blocking AKR1B1, which in turn prevents GC cells from undergoing the epithelial–mesenchymal transition. This discovery highlights Lut as a potential metabolic therapeutic drug and offers mechanistic insight into the evolution of gastric cancer caused by hyperglycemia.</p>

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Luteolin inhibits hyperglycemia-induced epithelial–mesenchymal transition and malignant progression in gastric cancer via targeting AKR1B1-mediated glucose metabolism

  • 期刊论文

  • 发表日期：

    2026年7月14日

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  • Qin He,
  • Feibao Tao,
  • Xiaowen Wen,
  • Liang Zhu,
  • Xuxing Ye

摘要

Gastric cancer (GC) is a very aggressive cancer with a high potential for metastasis. A naturally occurring flavonoid, luteolin (Lut) has metabolic regulation and anti-cancer properties. This work investigates whether Lut modulates glucose metabolism and targets AKR1B1 to prevent the epithelial-mesenchymal transition (EMT) in GC. Lut was used to treat human GC cell lines that were grown in both normal and high-glucose environments. Western blotting and qPCR were used to assess the expression levels of EMT markers and AKR1B1. The CCK-8 assay, the scratch assay, and the Transwell assay were used to measure cell movement, invasion, and proliferation, respectively. Metabolic flux analysis was used to measure fructose and lactate generation in order to assess glycolytic activity. We carried out AKR1B1 overexpression and knockdown experiments to elucidate the functional involvement of AKR1B1 in the action of Lut. In order to fully assess the anticancer effects of Lut and its underlying mechanisms, a high-glucose paradigm in nude mice was developed for in vivo validation. AKR1B1 expression was markedly elevated in GC cells under high-glucose circumstances, and this was accompanied by increased glycolytic activity. At the same time, the cells showed signs of EMT, including enhanced migratory and invasion capacities. Subsequent research showed that Lut therapy substantially alleviated anomalies in glucose metabolism by drastically suppressing AKR1B1 expression, downregulating important glycolytic enzymes, and reducing the generation of fructose and lactate. Additionally, by boosting E-cadherin expression, lowering vimentin and N-cadherin levels, and preventing cell migration and invasion, luteolin dramatically corrected high-glucose-induced EMT. The inhibitory effects of luteolin on glycolysis and EMT were largely offset by AKR1B1 overexpression, according to functional experiments; on the other hand, inhibition of AKR1B1 considerably reduces AKT pathway activation, which suppresses the malignant phenotype of gastric cancer cells. Together, these findings show how important AKR1B1 is to this regulatory axis. According to these results, luteolin inhibits high-glucose-induced metabolic reprogramming and EMT in gastric cancer cells via acting on AKR1B1, which lowers the cells’ capacity for metastasis. Lut may reduce the metabolic dysregulation brought on by hyperglycemia by blocking AKR1B1, which in turn prevents GC cells from undergoing the epithelial–mesenchymal transition. This discovery highlights Lut as a potential metabolic therapeutic drug and offers mechanistic insight into the evolution of gastric cancer caused by hyperglycemia.