Matairesinoside is a lignan extracted from the stem bark of Styrax japonica S. et Z, which is known to exhibit antibacterial and antioxidant properties while also functioning as a virus–cell fusion inhibitor. Matairesinoside acts as a potent inhibitor of TMEM16A, a novel target implicated in lung cancer progression, confirmed through molecular simulation and site-directed mutagenesis. Matairesinoside significantly reduces lung cancer cell growth, migration, and invasion while inducing apoptosis, with gene knockdown and overexpression demonstrating TMEM16A as the direct target and Western blot analysis elucidating the associated signaling pathways involved in tumor suppression.