BCAA metabolism promotes lung cancer tumorigenesis by enhancing cholesterol biosynthesis

  • Cell Rep. 2026 Jul 28;45(7):117641. doi: 10.1016/j.celrep.2026.117641.
Huimin Ma  1 ,  Erbao Zhang  2 ,  Jiaying Cai  2 ,  Dong Hang  2 ,  Xiaoyang Ma  2 ,  Yi Yang  2 ,  Meng Zhu  2 ,  Qi Sun  2 ,  Jianv Huang  2 ,  Jing Zhang  2 ,  Guang Huang  3 ,  Chang Zhang  2 ,  Chen Jin  2 ,  Yating Fu  2 ,  Lingnan Gong  2 ,  Chong Shen  4 ,  Xiangfeng Lu  5 ,  Yue Jiang  2 ,  Juncheng Dai  2 ,  Guangfu Jin  2 ,  Dongfeng Gu  6 ,  Xu Qian  7 ,  Hongbing Shen  8 ,  Hongxia Ma  9
Affiliations
  • 1. Department of Epidemiology, State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Zhejiang Key Lab of Vaccine, Infectious Disease Prevention and Control, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310000, China.
  • 2. Department of Epidemiology, State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
  • 3. Department of Health Inspection and Quarantine, Center for Global Health, School of Public Health, Key Lab of Modern Toxicology of Ministry of Education, Nanjing Medical University, Nanjing 211166, China.
  • 4. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
  • 5. Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100142, China.
  • 6. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100142, China.
  • 7. Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China.
  • 8. Department of Epidemiology, State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: [email protected].
  • 9. Department of Epidemiology, State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: [email protected].
PMID: 42397743 DOI: 10.1016/j.celrep.2026.117641
Abstract

Metabolic dysregulation has been established as a key driver in tumorigenesis, but its underlying mechanisms in Lung Cancer remain poorly characterized. In this study, we performed nested case-control analyses in two prospective cohorts (208 and 144 matched pairs) to examine associations between plasma metabolites and Lung Cancer risk. Untargeted metabolomics identified circulating metabolites of the branched-chain amino acid (BCAA) pathway as significantly associated with Lung Cancer risk. An animal study demonstrated that a high-BCAA diet accelerated Lung Cancer progression in the KrasG12D/+ mice model. Among the three BCAAs, leucine contributed much more to promoting Lung Cancer growth. Mechanistically, AUH-mediated acetyl-CoA production from leucine metabolism fuels Cholesterol synthesis, promoting lipid raft formation and EGFR redistribution and activation, thereby driving lung tumorigenesis. Moreover, atorvastatin blocked leucine-induced tumor progression in mice. Overall, our findings provide experimental evidence that leucine-driven BCAA metabolic reprogramming promotes lung tumorigenesis via Cholesterol metabolism, revealing a potential therapeutic target.

Keywords
AUH; CP: cancer; CP: metabolism; EGFR signaling; branched-chain amino acids; cholesterol; leucine; lung cancer; metabolomics; tumorigenesis.
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