Mitochondrial metabolic-transcriptional axis drives adaptive drug tolerance across major lung cancer subtypes.

Drug resistance remains the first and most significant barrier to long-term curative benefits in lung cancer patients. Traditional resistance mechanisms focused on oncogenic driver mutations are inadequate to explain reversible tumor phenotypic plasticity under therapeutic stress. Increasing evidence has placed mitochondrial metabolic rewiring as the core signaling hub bridging energy homeostasis to nuclear epigenetic reprogramming; however, a comparative review of this metabolic-transcriptional axis in lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and small cell lung cancer (SCLC) remains underrepresented. Here, this review integrates the published preclinical and translational data, dissecting how mitochondrial dysfunction, including altered oxidative phosphorylation (OXPHOS), TCA metabolite accumulation, ROS imbalance, and defective mitochondrial quality control, establishesdrug-tolerant persister (DTP) states. Subsequently, we elaborate on the conserved and subtype-specific genetic and epigenetic cascades induced by mtDNA variants, oncogenes (MYC/RAS), tumor suppressors (p53/LKB1), and oncometabolites (α-ketoglutarate, succinate, fumarate) that remodel chromatin landscapes and further initiate lineage plasticity, epithelial-mesenchymal transition, and immune evasion. We summarize promising mitochondrial-targeted interventions from OXPHOS inhibitors, fatty acid oxidation blockers, ROS modulators, and epigenetic agents and propose combinatorial therapeutic regimens according to the three lung cancer subtypes. This work establishes a unified metabolic-resilience framework and highlights multi-omics integrated profiling as a new paradigm in precision medicine to forecast resistance risk and reverse therapeutic failure in lung cancer.