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<p>Pulmonary fibrosis (PF) arises from persistent fibroblast activation and inflammation. Although microRNAs (miRNAs) are promising antifibrotic agents, the contribution of adipose-derived circulating miRNAs to PF remains unclear. Here, we identify brown adipose tissue (BAT) as a major source of exosomal miR-378a-3p that counteracts bleomycin (BLM)-induced PF. In fibrotic mice, BAT activity and circulating exosomal miR-378a-3p were reduced. Activating BAT by cold exposure or β3-adrenergic stimulation increased circulating and pulmonary miR-378a-3p and attenuated collagen deposition and inflammatory infiltration. Adipocyte-specific deletion of miR-378a-3p exacerbated lung inflammation and fibrosis, whereas lung-targeted overexpression of miR-378a-3p or intravenous delivery of BAT-derived exosomes enriched for miR-378a-3p ameliorated disease. Inhibition of exosome release from BAT lowered circulating miR-378a-3p and blunted the anti-fibrotic benefits of BAT activation, supporting a BAT-to-lung transfer mechanism. Mechanistically, miR-378a-3p targets <i>Itga5</i> to suppress FAK-PI3K-AKT signaling and limiting fibroblast activation, while simultaneously suppressing macrophage inflammatory responses by targeting <i>Fstl1</i> and suppressing NF-κB activation. Collectively, these findings identify miR-378a-3p as a BAT-derived signaling molecule with dual anti-inflammatory and anti-fibrotic effects in pulmonary fibrosis, expanding the pathophysiological scope of BAT-mediated inter-organ communication to lung disease.</p> Graphical Abstract <p></p>

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Circulating miR-378a-3p attenuates pulmonary inflammation and fibrosis via BAT-lung crosstalk

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月28日

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  • Rui He,
  • Xuemin Peng,
  • Ruping Pan,
  • Qianqian Kang,
  • Shulin Liu,
  • Min Yang,
  • Zhihan Wang,
  • Hongyan Deng,
  • Danpei Li,
  • Yuyu Xie,
  • Wenshe Wang,
  • Zengzhe Zhu,
  • Jiadai Liu,
  • Jing Ge,
  • Yulian Liu,
  • Ronghui Gao,
  • Yan Yang,
  • Yong Chen

摘要

Pulmonary fibrosis (PF) arises from persistent fibroblast activation and inflammation. Although microRNAs (miRNAs) are promising antifibrotic agents, the contribution of adipose-derived circulating miRNAs to PF remains unclear. Here, we identify brown adipose tissue (BAT) as a major source of exosomal miR-378a-3p that counteracts bleomycin (BLM)-induced PF. In fibrotic mice, BAT activity and circulating exosomal miR-378a-3p were reduced. Activating BAT by cold exposure or β3-adrenergic stimulation increased circulating and pulmonary miR-378a-3p and attenuated collagen deposition and inflammatory infiltration. Adipocyte-specific deletion of miR-378a-3p exacerbated lung inflammation and fibrosis, whereas lung-targeted overexpression of miR-378a-3p or intravenous delivery of BAT-derived exosomes enriched for miR-378a-3p ameliorated disease. Inhibition of exosome release from BAT lowered circulating miR-378a-3p and blunted the anti-fibrotic benefits of BAT activation, supporting a BAT-to-lung transfer mechanism. Mechanistically, miR-378a-3p targets Itga5 to suppress FAK-PI3K-AKT signaling and limiting fibroblast activation, while simultaneously suppressing macrophage inflammatory responses by targeting Fstl1 and suppressing NF-κB activation. Collectively, these findings identify miR-378a-3p as a BAT-derived signaling molecule with dual anti-inflammatory and anti-fibrotic effects in pulmonary fibrosis, expanding the pathophysiological scope of BAT-mediated inter-organ communication to lung disease.

Graphical Abstract