Rcn3, also known as Reticulocalbin 3, is an endoplasmic reticulum (ER) lumen-residing Ca2+ binding protein [3,4]. It is a member of the CREC family protein located in the secretory pathway of living cells, playing essential roles in protein biosynthesis processes [3,4]. Rcn3 has been implicated in multiple biological processes and disease-related pathways.

In pulmonary-related diseases, Rcn3 shows distinct effects. In idiopathic pulmonary fibrosis (IPF), Rcn3 upregulation is associated with fibrotic activation of lung fibroblasts. Rcn3 overexpression blunts the antifibrotic effects of pirfenidone and nintedanib, while repressing Rcn3 expression in mouse fibroblasts ameliorates bleomycin-induced lung fibrosis and pulmonary dysfunction in vivo, uncovering its role in the TGFβ1-RCN3-TGFBR1 positive feedback loop that promotes fibroblast activation [1]. In connective tissue disease-associated interstitial lung disease (CTD-ILD), serum Rcn3 level is higher compared to IPF patients and healthy controls, and it shows a negative correlation with pulmonary function indexes and a positive correlation with inflammatory indexes in CTD-ILD patients, suggesting its potential as a diagnostic biomarker [2]. In emphysema, Rcn3 expression is increased in COPD patients' lungs, and selective ablation of Rcn3 in type II alveolar epithelial cells (AECIIs) significantly alleviates the severity of mouse emphysema induced by intratracheal installation of porcine pancreatic elastase (PPE) [5].

In conclusion, Rcn3 is crucial in protein biosynthesis and has significant impacts on pulmonary-related diseases. The use of gene knockout (KO) and conditional knockout (CKO) mouse models has revealed its role in promoting fibroblast activation in IPF, as a potential diagnostic biomarker in CTD-ILD, and its contribution to emphysema development, providing valuable insights into disease mechanisms and potential therapeutic targets.