Natural products triggering non-apoptotic regulated cell death in lung cancer: A systematic review focusing on pyroptosis, with insights into cuproptosis and necroptosis

Lung cancer remains a leading cause of cancer mortality, and resistance to apoptosis limits the effectiveness of conventional and targeted therapies. This systematic review synthesized preclinical evidence on natural products that induce non-apoptotic regulated cell death in lung cancer, focusing on pyroptosis, cuproptosis, and necroptosis. Six databases were searched for original studies evaluating natural products, phytochemicals, plant extracts, or related bioactive compounds in lung cancer models. Overall, 25 studies met the inclusion criteria: 18 investigated pyroptosis, 5 investigated necroptosis, and 2 investigated cuproptosis. Because the included agents represented diverse chemical classes and most primary studies did not perform formal structure-activity relationship analyses, this review was designed as a mechanistic evidence map rather than a scaffold-optimization guide. Evidence was predominantly preclinical and focused on non-small cell lung cancer, especially A549-based models; 17 studies also included xenograft, allograft, or related animal experiments. Across chemically diverse agents, natural products were associated with reduced viability, proliferation, migration, invasion, colony formation, spheroid growth, metastasis, or tumor growth. Pyroptosis most frequently involved ROS/NF-κB/NLRP3/caspase-1/GSDMD signaling or caspase-3/GSDME activation. Cuproptosis studies highlighted copper accumulation, DLAT-associated mitochondrial stress, redox imbalance, and metabolic disruption, whereas necroptosis studies emphasized RIPK1/RIPK3-centered signaling with contributions from ROS, calcium flux, lysosomal injury, mitochondrial dysfunction, and autophagy. Overall, natural products show promise as multi-target modulators of non-apoptotic cell death in lung cancer, but the field remains clinically immature and requires further validation in standardized preclinical and clinical studies.