5-HT promotes bronchopulmonary dysplasia via TGM2-mediated serotonylation

  • iScience. 2025 Nov 19;28(12):114120. doi: 10.1016/j.isci.2025.114120.
Pengpeng Cai  1  2 ,  Ruidong Ding  1 ,  Chunyu Yin  1 ,  Xu Chen  1 ,  Yu Mao  1 ,  Keyu Lu  1 ,  Beibei Wang  1 ,  Yang Yang  1 ,  Mingshun Zhang  1  3 ,  Rui Cheng  1
Affiliations
  • 1. Department of Neonatal Medical Center, Children's Hospital of Nanjing Medical University, Nanjing, China.
  • 2. Department of Pediatrics, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China.
  • 3. NHC Key Laboratory of Antibody Technique, Jiangsu Key Laboratory of Pathogen Biology, Department of Immunology, Nanjing Medical University, Nanjing, China.
PMID: 41438086 DOI: 10.1016/j.isci.2025.114120
Abstract

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in preterm neonates. Untargeted metabolomics of serum samples revealed that tryptophan metabolism may be involved in the pathogenesis of BPD. Specifically, the serum level of 5-hydroxytryptamine (5-HT), a metabolite of tryptophan, is increased in preterm infants with BPD. Similarly, the pulmonary level of 5-HT is increased in a mouse model of hyperoxia-induced BPD. Administration of 5-HT directly impaired lung maturation. Tryptophan Hydroxylase 1 (TPH1) is the rate-limiting enzyme in the biosynthesis of 5-HT. As expected, the TPH1 inhibitor LP533401 mitigated lung injury in pups exposed to 85% oxygen. Mechanistically, 5-HT promotes post-translational serotonylation via Transglutaminase 2 (TGM2) in alveolar epithelial cells. TGM2 expression is increased in the pulmonary tissues of BPD-like mice. Blocking TGM2 partially reversed BPD-like damage to the lungs. Collectively, our findings highlight the roles of 5-HT and serotonylation in the pathogenesis of BPD.

Keywords
Developmental biology; Metabolomics.
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