2. Academic Validation
  3. Brain-derived neurotrophic factor and the derived dodecapeptide function as Toll-like receptor 4 antagonists in acute lung injury

Brain-derived neurotrophic factor and the derived dodecapeptide function as Toll-like receptor 4 antagonists in acute lung injury

  • Nat Commun. 2026 Feb 14;17(1):2786. doi: 10.1038/s41467-026-69541-7.
Weiwei Zhu # 1 2 3,  Leiming Jin # 2,  Qianhui Zhang # 2,  Yaqian Cui # 2,  Yu Zou 1 2,  Pan Chen 1 2,  Jiaxi Ye 2,  Yongqiang Xiong 1 2,  Mengsha Lin 2,  Yongqiang Zhou 4,  Renlv Wu 3,  Yan Liang 3,  Zaishou Zhuang 3,  Joo Young Huh 5,  Wu Luo 6 7 8,  Guang Liang 9 10 11
Affiliations

Affiliations

  • 1 Department of Cardiology and Medical Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3 Affiliated Cangnan Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4 Department of Chemoradiation Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 5 College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
  • 6 Department of Cardiology and Medical Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • 7 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • 8 Affiliated Cangnan Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • 9 Department of Cardiology and Medical Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • 10 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • 11 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 41690930 DOI: 10.1038/s41467-026-69541-7
Abstract

The neurotrophic factor (NTF) family has recently expanded its role beyond neurological conditions, but its involvement in acute inflammatory lung diseases remains largely unclear. Using well-established acute lung injury (ALI) and sepsis models, we demonstrate that brain-derived neurotrophic factor (BDNF), a key NTF, is impaired in pulmonary epithelial cells and negatively correlates with the inflammatory response. Raising the BDNF level alleviates inflammatory lung injury, but these effects are absent in macrophage-deleted mice. Both in vivo and in vitro results show BDNF inhibits macrophage inflammation, and further proteomics analysis identifies macrophage TLR4 as a receptor that BDNF antagonizes via direct binding. The BDNF fragment (aa 104-115) is critical for BDNF-TLR4 interaction, and the corresponding synthetic BDNF-derived dodecapeptide (BDP-12) retains TLR4-antagonistic and anti-inflammatory effects both in vitro and in vivo, without pro-proliferative side effects. In conclusion, our findings reveal that epithelial-derived BDNF prevents macrophage inflammation by directly targeting TLR4 and highlights BDP-12 as a potential therapeutic agent for acute inflammatory diseases.

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