Beyond gene signatures: a mechanism-based framework for cuproptosis susceptibility in non-small cell lung cancer at...

Non-small cell lung cancer (NSCLC) has become a biomarker-driven disease, yet durable control remains limited by therapeutic resistance, metabolic heterogeneity, and incomplete predictors of response. Cuproptosis, a copper-dependent form of regulated cell death linked to mitochondrial respiration and lipoylated TCA-cycle proteins, offers a potential metabolic layer for patient stratification. However, the current NSCLC literature is dominated by cuproptosis-related gene scores, lncRNA models, and immune-association signatures. These studies are useful for hypothesis generation but rarely demonstrate copper flux, FDX1 dependence, lipoylated DLAT/DLST engagement, iron-sulfur cluster protein loss, or pathway-specific pharmacodynamics. We therefore organize the NSCLC literature using a mechanistic evidence matrix that separates transcriptomic association, copper-access enrichment, mitochondrial-dependence evidence, canonical target engagement, and clinical pharmacodynamic confirmation. Rather than proposing a new molecular subtype or diagnostic label, we conceptualize cuproptosis susceptibility as a continuous, mechanism-based construct defined by copper access, TCA/OXPHOS dependence, lipoylated substrate burden, detoxification capacity, and immune context. This framework reframes cuproptosis from universal copper toxicity to a conditional therapeutic vulnerability. Its clinical value will depend on biomarker-enriched trials with pharmacodynamic confirmation rather than retrospective gene signatures alone.