| Title: | BCAA metabolism promotes lung cancer tumorigenesis by enhancing cholesterol biosynthesis |
| Journal: | Cell Reports |
| Published: | 3 Jul 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42397743/ |
| DOI: | https://doi.org/10.1016/j.celrep.2026.117641 |
Publication 20443
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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.</p>
24 Authors
- Huimin Ma
- Erbao Zhang
- Jiaying Cai
- Dong Hang
- Xiaoyang Ma
- Yi Yang
- Meng Zhu
- Qi Sun
- Jianv Huang
- Jing Zhang
- Guang Huang
- Chang Zhang
- Chen Jin
- Yating Fu
- Lingnan Gong
- Chong Shen
- Xiangfeng Lu
- Yue Jiang
- Juncheng Dai
- Guangfu Jin
- Dongfeng Gu
- Xu Qian
- Hongbing Shen
- Hongxia Ma
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