Herbal Formula Yi‐Fei‐Jie‐Du‐Tang Regulates Epithelial‐Mesenchymal Transition and Vasculogenic Mimicry in Lung Cancer via HIF1A‐Mediated Ferroptosis

Abstract Traditional Chinese medicine (TCM) Yi‐Fei‐Jie‐Du‐Tang (YFJDT) has shown potential in lung cancer treatment. However, the mechanisms underlying the effects of YFJDT on lung cancer remain unclear. Bioinformatics analysis is conducted to identify potential targets of YFJDT. The impact of YFJDT on hypoxia‐inducible factor 1 alpha (HIF1A), ferroptosis, and vasculogenic mimicry (VM) is investigated using xenograft tumor models and A549 cells. Additionally, A549 cells are stimulated with CoCl₂ to mimic the hypoxic microenvironment of the tumor. The role of HIF1A overexpression in modulating ferroptosis is assessed. The effects of HIF1A and ferroptosis on epithelial‐mesenchymal transition (EMT) and VM in vitro are evaluated. Results: YFJDT treatment led to a concentration‐dependent decrease in HIF1A levels in xenograft tumors and A549 cells. Overexpression of HIF1A counteractes the inhibitory effects of YFJDT on proliferation, EMT, and VM in transplanted tumors. Moreover, HIF1A overexpression attenuates YFJDT‐induced lipid peroxidation and iron accumulation, indicating inhibition of ferroptosis in A549 cells. Hypoxia‐induced alterations in EMT markers and VM are reversed by YFJDT but exacerbated by HIF1A overexpression. Molecular docking identified salicylic acid and psoralen as potential components of YFJDT targeting HIF1A. YFJDT exerts anti‐tumor effects in lung cancer by downregulating HIF1A and promoting ferroptosis.