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<p>Metabolic reprogramming is a core hallmark of cancer, yet how it contributes to the clinical heterogeneity of lung adenocarcinoma (LUAD) remains poorly understood. Here, by applying unsupervised clustering to the metabolic transcriptomes of 510 LUAD tumours, we identify two robust and prognostically significant subtypes. We show that these subtypes have divergent clinical outcomes, with subtype-1 patients exhibiting significantly longer overall and disease-specific survival compared to the more aggressive subtype-2. This clinical distinction is underpinned by fundamentally different metabolic architectures: the aggressive subtype-2 is characterized by the upregulation of central carbon metabolism, including the citric acid cycle and respiratory electron transport, whereas the less aggressive subtype-1 shows a distinct enrichment for choline catabolism. Consistent with this, Cox regression analysis reveals that high expression of the TCA cycle enzyme OGDH is a top predictor of increased disease risk, while the glycolytic enzyme PGK1 is associated with a decreased risk. Our findings establish a direct link between transcriptional metabolic states and patient survival in LUAD, defining a framework for prognostic stratification and identifying subtype-specific metabolic vulnerabilities for therapeutic targeting.</p>

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Metabolic pathway signatures define prognostic subtypes of lung adenocarcinoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月23日

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  • Doris Kafita,
  • Zitha Mukwamba,
  • Vanity Mapulanga,
  • Adon Chawe,
  • Musalula Sinkala

摘要

Metabolic reprogramming is a core hallmark of cancer, yet how it contributes to the clinical heterogeneity of lung adenocarcinoma (LUAD) remains poorly understood. Here, by applying unsupervised clustering to the metabolic transcriptomes of 510 LUAD tumours, we identify two robust and prognostically significant subtypes. We show that these subtypes have divergent clinical outcomes, with subtype-1 patients exhibiting significantly longer overall and disease-specific survival compared to the more aggressive subtype-2. This clinical distinction is underpinned by fundamentally different metabolic architectures: the aggressive subtype-2 is characterized by the upregulation of central carbon metabolism, including the citric acid cycle and respiratory electron transport, whereas the less aggressive subtype-1 shows a distinct enrichment for choline catabolism. Consistent with this, Cox regression analysis reveals that high expression of the TCA cycle enzyme OGDH is a top predictor of increased disease risk, while the glycolytic enzyme PGK1 is associated with a decreased risk. Our findings establish a direct link between transcriptional metabolic states and patient survival in LUAD, defining a framework for prognostic stratification and identifying subtype-specific metabolic vulnerabilities for therapeutic targeting.