Dietary intake and BCAA metabolism regulate pulmonary fibrosis through KDM4A-mediated epigenetic remodeling in male mice
Idiopathic pulmonary fibrosis is a progressive and fatal disorder characterized by abnormal activation of alveolar fibroblasts. However, the metabolic reprogramming of alveolar fibroblasts during lung injury remains unclear. Here we show that uptake of branched-chain amino acids is increased, whereas their catabolism is significantly impaired in fibrotic lung fibroblasts and mouse lung tissues. Branched-chain amino acids promote lung fibroblast activation and bleomycin-induced lung fibrosis. Genetic inactivation of branched-chain amino acid transaminase 2 exacerbates fibrosis, whereas inhibition of the corresponding transporter SLC7A5 or enhancement of catabolism attenuates pulmonary fibrosis in male mice. Mechanistically, ATF4 and PPARγ regulate the expression of SLC7A5 and BCAA catabolic genes, respectively. We identify KDM4A as a key mediator of the epigenetic regulation of fibrotic genes. Notably, dysregulated BCAA metabolism is associated with disease severity in patients, suggesting that targeting BCAA metabolism may serve as a promising therapeutic strategy for idiopathic pulmonary fibrosis.
Authors
- Wei Kevin Zhang (ORCID: https://orcid.org/0000-0003-4960-6137)
- Bingpeng Guo (ORCID: https://orcid.org/0000-0002-8205-0321)
- Mingmeng Fang
- Yang Peng (ORCID: https://orcid.org/0000-0002-2113-5858)
- Zhili Rong (ORCID: https://orcid.org/0000-0002-1699-7074)
- Chaoqun Wang (ORCID: https://orcid.org/0000-0003-0415-6080)
- Wenxiang Hu
- Na He
- Chuanfei Zeng
- Wanli Peng
- Huimin Huang
- Lian Yang
- Miao Lei
- Jie Lv
- Jie Yao
- Cuihua Wang
- Wei Rao
- Zexian Ou (ORCID: https://orcid.org/0009-0002-7495-6905)
- Qian Han
- Shuang Wu
- Su Fang
- Penghui Yang
Institutions
- University of Science and Technology of China (CN)
- Sun Yat-sen University (CN)
- Yunnan University (CN)
- Chinese Academy of Sciences (CN)
- ShanghaiTech University (CN)
- Guangzhou Experimental Station (CN)
- First Affiliated Hospital of Guangzhou Medical University (CN)
- Guangdong-Hongkong-Macau Joint Laboratory of Collaborative Innovation for Environmental Quality (CN)
- Shanghai Institute of Materia Medica (CN)
- State Key Laboratory of Respiratory Disease (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Southern Medical University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-27
- DOI
- https://doi.org/10.1038/s41467-026-72273-3
- Primary Topic
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China