The newly identified EPB41L4A-AS2/TGFBR1/SMAD2/SMAD3 axis sheds light on a novel molecular mechanism for HNSCC cell metastasis, indicating that EPB41L4A-AS2 is a valuable biomarker and a promising therapeutic target for the management of HNSCC. Here, SMAD3 is linked to head and neck squamous cell carcinoma.