Deoxylapachol inhibits esophageal squamous cell carcinoma progression via targeting FOXM1-mediated Wnt/β-catenin pathway

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a significant global health challenge. Deoxylapachol (DEO) is a natural quinone compound from the Cichorium glandulosum Boiss. et Huet. However, the effects and potential mechanisms of DEO against ESCC remain unclear. PURPOSE: To investigate the effects and potential mechanisms of DEO against ESCC. METHODS: Bioinformatics analysis, Western blot, qRT-PCR, colony formation, EdU, molecular docking, molecular dynamics (MD), surface plasmon resonance (SPR), immunohistochemistry, transmission electron microscopy and a xenograft mouse model were used in this study. RESULTS: DEO significantly suppressed ESCC cell migration and invasion while inducing ferroptosis and cytoplasmic alkalization, accompanied by elevated reactive oxygen species (ROS) generation. Bioinformatics analysis identified FOXM1 as a core potential target of DEO and revealed the involvement of the Wnt/β-catenin pathway in its anti-ESCC mechanism. Molecular docking, MD simulations, and SPR analysis confirmed that DEO directly targets FOXM1. Moreover, FOXM1, MYBL2, and CDCA3 were found to be positively correlated and overexpressed in human ESCC tissues. DEO treatment markedly downregulated their expression, which was associated with the inhibition of malignant phenotypes. Mechanistically, the inhibition of ESCC progression by DEO might be mediated through the targeting of FOXM1, concomitant downregulation of MYBL2 and CDCA3, and subsequent suppression of the Wnt/β-catenin pathway, as validated by combined shFOXM1 and oeFOXM1 approaches. CONCLUSION: Our study is the first to demonstrate the potent anti-ESCC effects of DEO. The results indicate DEO may inhibit ESCC progression through targeting FOXM1-mediated Wnt/β-catenin pathway, positioning DEO as a promising candidate for the development of novel ESCC therapeutics.