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Background <p>Nasopharyngeal carcinoma (NPC) is a highly prevalent malignant epithelial tumor in southern China. Although early-stage NPC patients have a favorable prognosis with concurrent chemoradiotherapy, the limited efficacy of current clinical regimens remains a crucial obstacle in the treatment of advanced NPC patients. 5-Methoxyflavone, a methylated flavonoid, has been reported to exhibit diverse roles in anti-cancer activity and lipid modulation. However, its potential role in NPC remains unclear. This study aims to investigate the effect of 5-Methoxyflavone on NPC proliferation and its underlying mechanism.</p> Methods <p>MTT, colony formation, EdU assays, and flow cytometry were performed with various concentrations of 5-Methoxyflavone (0, 40, 60, 80 and 100 µM) to investigate its effect on NPC cell proliferation. A HONE1 xenograft model was established for in vivo validation. Immunoprecipitation and dual-luciferase reporter assay were employed to confirm 5-Methoxyflavone’s regulatory function on the p53/SREBPs pathway. Lipid synthesis was determined by measuring total cholesterol and triglycerides using ELISA and visualizing lipid droplets via Oil Red O staining. Ferroptosis was evaluated by detecting intracellular ferrous ions, lipid ROS, and glutathione (GSH) levels.</p> Results <p>5-Methoxyflavone suppressed NPC cell proliferation in a concentration-dependent manner in vitro. In addition, it profoundly inhibited tumor xenograft growth in mice without causing obvious adverse toxicity. Mechanistically, 5-Methoxyflavone deubiquitinated and stabilized p53 via inhibiting MDM2 expression, leading to suppression of SREBPs and their downstream lipid synthesis-related genes, thus inhibiting lipid synthesis in NPC cells. p53 depletion counteracted 5-Methoxyflavone’s inhibitory effect, while SREBP1 knockdown restored proliferation in p53-silenced cells. Furthermore, 5-Methoxyflavone-stimulated downregulation of SREBP1/SCD signaling triggered ferroptosis in NPC cells by promoting iron accumulation, lipid peroxidation, and GSH depletion. Overexpression of SCD reversed the ferroptosis-inducing effects of 5-Methoxyflavone.</p> Conclusions <p>Our findings reveal that 5-Methoxyflavone inhibits NPC proliferation by blocking lipid synthesis and inducing ferroptosis via the p53/SREBPs/SCD signaling pathway, providing evidence for the development of innovative drugs for NPC treatment.</p>

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5-Methoxyflavone suppresses nasopharyngeal carcinoma proliferation through regulating p53/SREBP/SCD signaling-mediated lipid synthesis and ferroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月18日

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  • Yiwen Cui,
  • Yan Zhao,
  • Rong Li,
  • Mingyong Li,
  • Tongyuan Deng,
  • Bo Bao,
  • Yingying Hu

摘要

Background

Nasopharyngeal carcinoma (NPC) is a highly prevalent malignant epithelial tumor in southern China. Although early-stage NPC patients have a favorable prognosis with concurrent chemoradiotherapy, the limited efficacy of current clinical regimens remains a crucial obstacle in the treatment of advanced NPC patients. 5-Methoxyflavone, a methylated flavonoid, has been reported to exhibit diverse roles in anti-cancer activity and lipid modulation. However, its potential role in NPC remains unclear. This study aims to investigate the effect of 5-Methoxyflavone on NPC proliferation and its underlying mechanism.

Methods

MTT, colony formation, EdU assays, and flow cytometry were performed with various concentrations of 5-Methoxyflavone (0, 40, 60, 80 and 100 µM) to investigate its effect on NPC cell proliferation. A HONE1 xenograft model was established for in vivo validation. Immunoprecipitation and dual-luciferase reporter assay were employed to confirm 5-Methoxyflavone’s regulatory function on the p53/SREBPs pathway. Lipid synthesis was determined by measuring total cholesterol and triglycerides using ELISA and visualizing lipid droplets via Oil Red O staining. Ferroptosis was evaluated by detecting intracellular ferrous ions, lipid ROS, and glutathione (GSH) levels.

Results

5-Methoxyflavone suppressed NPC cell proliferation in a concentration-dependent manner in vitro. In addition, it profoundly inhibited tumor xenograft growth in mice without causing obvious adverse toxicity. Mechanistically, 5-Methoxyflavone deubiquitinated and stabilized p53 via inhibiting MDM2 expression, leading to suppression of SREBPs and their downstream lipid synthesis-related genes, thus inhibiting lipid synthesis in NPC cells. p53 depletion counteracted 5-Methoxyflavone’s inhibitory effect, while SREBP1 knockdown restored proliferation in p53-silenced cells. Furthermore, 5-Methoxyflavone-stimulated downregulation of SREBP1/SCD signaling triggered ferroptosis in NPC cells by promoting iron accumulation, lipid peroxidation, and GSH depletion. Overexpression of SCD reversed the ferroptosis-inducing effects of 5-Methoxyflavone.

Conclusions

Our findings reveal that 5-Methoxyflavone inhibits NPC proliferation by blocking lipid synthesis and inducing ferroptosis via the p53/SREBPs/SCD signaling pathway, providing evidence for the development of innovative drugs for NPC treatment.