Thoracic tumors, including lung adenocarcinoma (LUAD) and malignant pleural mesothelioma (MM), remain a leading cause of cancer-related deaths, primarily due to the challenges in treating advanced thoracic tumors. New drugs with optimal efficacy and minimal side effects are required. Traditional Chinese Medicine (TCM) compounds offer a promising alternative. Our study explores the effectiveness of the TCM compound Narciclasine against LUAD and MM. Spheroids derived from LUAD (A549, LuCa1) and MM (MSTO-211H, H2052/484) cell lines were treated with Narciclasine, and efficacy was evaluated through cell morphology analysis, intracellular adenosine triphosphate (ATPi) and lactate dehydrogenase (LDH) assays, RT-qPCR, and western blot analysis. Narciclasine reduced cell viability, with an 80% reduction in viability in MM. It induced cell apoptosis and inhibited proliferation. The IC₅₀ values for Narciclasine ranged from 50 to 150 nM. In silico analysis identified shared gene targets between Narciclasine, LUAD, and MM. Narciclasine modulated the expression of genes associated with ferroptosis and cuproptosis, and the epithelial-to-mesenchymal transition. Narciclasine shows promising efficacy against LUAD and MM spheroid models. These findings warrant further investigation into the mechanisms of action and potential clinical application of Narciclasine for treating thoracic malignancies, offering hope for improved therapeutic options and patient outcomes.