Secreted RCN3 acts as an early epithelial-fibroblast mediator via TGFβR1-Smad signaling in post-ALI pulmonary fibrosis

  • Cell Commun Signal. 2026 Feb 9;24(1):167. doi: 10.1186/s12964-026-02690-w.
Xiaoqian Shi  1 ,  Zhenyan Wang  1 ,  Fangping Ding  2 ,  Runlin Z Ma  3 ,  Jing Wang  4 ,  Yingmin Ma  2 ,  Jiawei Jin  5  6
Affiliations
  • 1. Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
  • 2. Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Beijing Institute of Hepatology, Capital Medical University, Beijing, China.
  • 3. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  • 4. Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
  • 5. Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. [email protected].
  • 6. Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. [email protected].
PMID: 41664195 DOI: 10.1186/s12964-026-02690-w
Abstract

Pulmonary fibrosis (PF), driven by dysregulated epithelial-fibroblast interactions, contributes to poor outcomes after acute pneumonia. However, early profibrotic paracrine mediators released by injured epithelium remain incompletely defined. Using secretomics of LPS-treated pulmonary epithelial cells, we identified Reticulocalbin 3 (RCN3) as an epithelial paracrine mediator. In clinical bronchoalveolar lavage fluid (BALF) samples, RCN3 was significantly higher in organizing pneumonia patients undergoing active fibrotic organization than in idiopathic PF patients in a stable fibrotic state. In LPS-induced acute lung injury (ALI) mice, BALF RCN3 peaked earlier than TGFβ1/FGF2/CTGF, indicating an early role in PF. Mechanistically, epithelial RCN3 is secreted via an N140-glycosylation–dependent ER-Golgi pathway and engages TGFβR1, activating canonical SMAD2/3 signaling in fibroblasts; RCN3 also upregulates TGFβ1 and TGFβR1/2 in a Smad3-dependent manner. In vivo, intratracheal exogenous RCN3 administration, in the absence of LPS, was sufficient to trigger fibrosis, whereas early-phase neutralization of RCN3 after LPS-ALI attenuated fibrotic remodeling. Collectively, these findings identify secreted, stress-responsive RCN3 as an early epithelial paracrine mediator engaging TGFβR1-Smad2/3 signaling and nominate it as a potential early-window therapeutic target for post-ALI pulmonary fibrosis.

Keywords
Acute respiratory distress syndrome (ARDS); Organizing pneumonia (OP); Pulmonary fibrosis; Reticulocalbin 3 (RCN3); TGFβ receptor type 1 (TGFβR1).
Products