Tetrandrine Alleviates Pulmonary Fibrosis by Modulating Lung Microbiota‐Derived Metabolism and Ameliorating Alveolar Epithelial Cell Senescence

ABSTRACT Tetrandrine (TET) is a minimally toxic drug extracted from the root of Stephania tetrandra. We previously demonstrated that TET could ameliorate pulmonary fibrosis (PF) by modulating autophagy. However, the mechanism behind TET's protective effects on PF remains unclear. In this study, we utilized 16S rRNA gene sequencing, nontargeted metabolomic analysis, and network pharmacology to identify changes in lung microbiota and metabolites that mediate alveolar epithelial cell senescence in bleomycin (BLM)‐induced PF in mice. Additionally, we employed Western blot analysis, RT‐PCR, and immunofluorescence staining to investigate the in vitro and in vivo effects of TET and its influential bacterial metabolites on PF. The TET intervention alleviated PF by regulating the compositions of lung microbial communities ( Streptococcus , Micrococcus , Acinetobacter , Altererythrobacter , Atopostipes , Candidatus Cloacimonas , Clostridium sensu stricto 1 , Sphingomonas , Listeria , Blautia , and Pseudomonas ) and metabolites (3,4‐dihydroxyphenylpropionic acid (3,4‐DHPPA), 6‐Aminonicotinamide, N‐acetyl‐5‐methoxykynuramine, and resiniferatoxin). Through network pharmacological analysis, it was determined that 3,4‐DHPPA played a crucial role in alleviating PF by further inhibiting the senescence of alveolar epithelial cells, a finding further validated in ex vivo experiments. TET mitigated BLM‐induced PF in murine models through the modulation of lung microbiota composition and metabolism. Specifically, TET augmented the level of the microbiota‐derived metabolite, 3,4‐DHPPA, which in turn attenuated alveolar epithelial cell senescence.