In summary, our manuscript suggested LEF1-AS1 as a novel biomarker for HNSCC, illustrated the effects of LEF1-AS1, miR-221-5p, and GJA1 on hypopharyngeal squamous cell carcinoma for the first time, and revealed that the LEF1-AS1/miR-221-5p/GJA1 axis may serve as a novel promising target for HSCC therapy. Here, LEF1 is linked to hypopharynx squamous cell carcinoma.