TCM-Derived Small Molecules Targeting Metabolic Vulnerabilities in NSCLC: Ferroptosis-Centered Mechanisms and Emerging Cuproptosis- and Disulfidptosis-Related Vulnerabilities.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide and is characterized by therapeutic resistance, metabolic plasticity, and immune evasion. Accumulating evidence indicates that metabolic reprogramming not only supports tumor growth but also creates exploitable vulnerabilities linked to regulated cell death. Traditional Chinese medicine (TCM)-derived small molecules have attracted increasing attention owing to their structural diversity, multitarget properties, and broad pharmacological activities. In this review, we summarize recent advances in TCM-derived compounds targeting metabolism-associated regulated cell death in NSCLC, with a primary focus on ferroptosis and a cautious discussion of emerging cuproptosis- and disulfidptosis-related mechanisms. Ferroptosis has been extensively investigated in this context, with natural compounds shown to induce cell death through coordinated regulation of cystine transport, glutathione metabolism, GPX4 activity, iron homeostasis, and lipid peroxidation. In parallel, emerging studies suggest that certain natural products may influence copper-dependent cell death pathways and metabolic states associated with disulfide stress. These processes are closely linked to distinct metabolic features of NSCLC, including lipid dependency, copper homeostasis, and glucose utilization. Finally, we discuss major challenges for clinical translation, including poor bioavailability, off-target toxicity, insufficient biomarker stratification, and limited high-quality evidence, and highlight emerging strategies such as nanodelivery systems, structural optimization, and targeted protein degradation approaches. Overall, TCM-derived small molecules represent a promising source of metabolism-targeted therapeutics and provide a foundation for further exploration of regulated cell death in NSCLC. Current evidence is strongest for ferroptosis induction, whereas cuproptosis- and disulfidptosis-related mechanisms remain emerging areas that require further experimental validation in NSCLC models.