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The protective effect of the M. calabura Linn. fruit ethanolic extract (MFEE) against nickel (Ni)-induced vascular endothelial growth factor (VEGF) expression in hepatocellular carcinoma (HepG2) cells was investigated. MFEE contained 4 flavonoids: epicatechin, rutin, diosmin and luteolin, and 11 phenolic acids: gallic acid, gentisic acid, p-hydroxybenzoic acid, vanillic acid, p-coumaric acid, ferulic acid, sinapic acid, syringic acid, p-anisic acid and rosmarinic acid. Substantial VEGF expression was assayed in Ni-stimulated HepG2 cells, which was significantly suppressed through MFEE treatment via down-regulating Raf-1 proto-oncogene, serine/threonine kinase (RAF1) /mitogen-activated protein kinase 1/2 (MEK1/2)/extracellular-signal-regulated kinase 1/2 (ERK1/2), and Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) pathways as well as inhibiting hypoxia-inducible factor (HIF)-1α expression down-regulated by phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. The results showed that MFEE should have the potential to lower liver cancer risk in the Ni-polluted environment by suppressing VEGF expression.