Naringin nanoparticles alleviate RA-ILD pulmonary fibrosis by targeting 14-3-3ζ to inhibit LYVE1+ macrophages TGF-β1 secretion

Rheumatoid arthritis (RA)–interstitial lung disease (RA-ILD) is an idiopathic complication of RA that presents as pulmonary fibrosis. Despite extensive research, the exact cause of RA-ILD remains elusive, driving the ongoing search for effective treatments. Transcriptomes of lung tissues from both healthy individuals and patients with RA-ILD were analyzed to identify differentially expressed genes. CMAP identified the flavonoid naringin (NAR) as a potential drug for RA-ILD treatment. Subsequently, NAR nanoparticles were developed and orally administered to a collagen-induced arthritis ILD (CIA-ILD) model in DBA/1 mice. Transcriptome and protein profiling analyses using microscale thermophoresis and cellular thermal shift analysis were conducted to predict and confirm the downstream molecules and targets of NAR therapy in RA-ILD. Additionally, an in vitro pulmonary fibrosis model was established to investigate the specific mechanism of NAR treatment in CIA-ILD. In animal experiments, treatment with NAR nanoparticles significantly reduced pulmonary fibrosis in CIA-ILD mice compared with untreated mice. Moreover, there was a notable increase in the number of lymphatic vessel endothelial receptor-1 positive (LYVE1 + ) macrophages in the lung tissue. Mechanistically, NAR increased LYVE1 levels in macrophages by targeting 14-3-3 zeta. In vitro experiments demonstrated that NAR-treated LYVE1 + bronchoalveolar macrophages (LYVE1 + BLM) effectively inhibited epithelial-mesenchymal transition of A549 cells and fibroblast-myofibroblast transition of HFL1 cells by reducing the secretion of transforming growth factor beta-1. Our research revealed NAR as a novel reference drug for treating RA-ILD, while also identifying potential therapeutic target cells and avenues for drug development in this context. Further comprehensive research is warranted to extend these findings and benefit a broader population of patients with RA-ILD pulmonary fibrosis. • Naringin nanopaticles alleviate pulmonary fibrosis in CIA-ILD mice. • Naringin targets lung macrophages 14-3-3ζ to affect LYVE1 expression. • LYVE1 hi lung macrophages reduce TGF-β1 secretion. • TGF-β1 promotes pulmonary fibrosis in RA-ILD patients by affecting lung epithelial cell EMT and lung fibroblast FMT.