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However, these alterations are highly heterogeneous across cancer types, and current treatments rarely exploit subtype-specific metabolic vulnerabilities. To address this gap, we developed a unified bioinformatics framework that integrates transcriptomic profiling (UALCAN), drug\u2013gene interactions (DGIdb), gene\u2013disease associations (Open Targets), pathway enrichment (Enrichr), and protein\u2013protein interaction networks (STRING\/Cytoscape). This pipeline was applied to lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LSCC), breast cancer (BRCA), and metastatic breast tumors (MET500) to uncover cancer type\u2013specific metabolic programs and prioritize translational targets. Our analysis revealed distinct signatures: LUAD showed glycolytic activation, LSCC coupled glycolysis with oxidative phosphorylation, BRCA favored anabolic and lipogenic pathways, and MET500 tumors adopted stress-adaptive states with elevated antioxidant and autophagy programs. Integration of pharmacological evidence highlighted clinically actionable interactions between metabolic genes and FDA-approved drugs, including ASNS\u2013asparaginase, DHODH\u2013teriflunomide, and G6PD\u2013rasburicase. Gene\u2013disease associations further prioritized G6PD, SLC2A1, and TK1 as robust targets strongly linked to lung and breast cancers. Pathway enrichment pinpointed the pentose phosphate pathway, pyrimidine metabolism, and glutathione metabolism as conserved axes sustaining tumor survival, while network analysis positioned the G6PD\u2013PGD hub as a central metabolic node connecting glucose uptake, redox balance, and nucleotide biosynthesis. To place these bioinformatics-derived findings within a functional and clinical context, we complemented the computational analyses with patient survival assessment, clinical trial screening, and targeted literature appraisal. Survival analysis demonstrated cancer type\u2013specific prognostic relevance for selected metabolic genes, while clinical and literature-based screening revealed both ongoing translational efforts and substantial gaps between computational target prioritization and experimental or clinical validation. This integrative analysis shows that cancer metabolism is altered in subtype-specific ways that can be systematically mapped to reveal potential therapeutic targets. By linking transcriptomic evidence with drug\u2013gene interactions and clinical context, this framework provides a scalable approach for cancer metabolism research and supports the prioritization of pathways with potential translational relevance.<\/jats:p>","DOI":"10.1371\/journal.pone.0350628","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:27:26Z","timestamp":1780594046000},"page":"e0350628","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mapping metabolic reprogramming in lung and breast cancer through integrative 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