Taken together, we demonstrated for the first time that the novel microtubule Inhibitor MPT0B098 inhibits hypoxia-induced EMT in HNSCC through modulation of HIF-1α, Twist, SNAI2/Slug, TGF-β/Smad signaling, and FAK/actin cytoskeleton rearrangement. The gene discussed is TGFB1; the disease is head and neck squamous cell carcinoma.