Natural isoflavone sophoricoside emerges as a therapeutic candidate for lung cancer targeting TMEM16A ion channel

Background The incidence and mortality rates of lung cancer have consistently ranked highest among all cancers for an extended period. Identifying specific targets and developing effective drugs is crucial. In this study, we discovered that the natural compound sophoricoside, derived from Sophora japonica, targets the TMEM16A ion channel for lung cancer treatment. Methods Whole-cell patch clamp experiments were conducted to evaluate the inhibitory efficacy of sophoricoside on TMEM16A. Molecular dynamics simulations were performed to predict the affinity and the gating-related conformational changes of sophoricoside within TMEM16A. Cell proliferation, migration, and apoptosis experiments were employed to detect the regulation of sophoricoside on lung cancer cell growth. Western blot analyses were carried out to investigate the signaling mechanisms underlying the regulation of lung cancer growth by sophoricoside. In vivo xenograft tumor models were utilized to evaluate the anticancer efficacy and biosafety profile of sophoricoside. Results Sophoricoside inhibited the TMEM16A whole-cell current in a concentration-dependent manner, with an IC 50 of 14.8 ± 1.2 μM. Molecular dynamics simulations confirmed that sophoricoside bond to the extracellular vestibular region of TMEM16A, blocking chloride ion transport by inducing constriction of the hydrophobic pore regions. Subsequently, we investigated the regulatory effects of varying concentrations of sophoricoside on the growth of LA795 cells. Knocking down TMEM16A in LA795 cells and overexpressing TMEM16A in 16HBE cells established that TMEM16A was a critical target of sophoricoside. Western blot experiments demonstrated that sophoricoside inhibited the growth of LA795 cells via the several signal transduction pathways. In vivo results revealed that sophoricoside exhibits both potent anticancer effects and satisfactory biosafety. Conclusion This study identifies the natural product sophoricoside as a potential agent targeting TMEM16A to inhibit lung cancer growth, presenting a promising candidate for lung cancer treatment drugs.