Objective To exploring the mechanism of Jinshui Chenfei formula(JCF)in ameliorating silica(SiO2)-induced silicosis fibrosis based on endogenous metabolite changes.Methods A total of 32 SPF male Sprague-Dawley(SD)rats were divided into normal control group,model group,JCF group(9.72 g·kg-1·d-1),and Tetrandrine group(27 mg·kg-1·d-1)according to random number table method.The experimental silicosis model was established by intratracheal injection with SiO2 suspension(250 mg/kg)on day 1.From week 5-8,silicosis rats were treated with tetrandrine or JCF.On the end of week 8,the changes of pulmonary function index,including forced vital capacity(FVC),tidal volume(TV)and lung dynamic compliance(Cydn)were detected.The pathological changes of lung tissue were analyzed by hematoxyline-osin(HE)staining and Masson staining,the severity of focal alveolitis and fibrosis was also evaluated using the Szapiel scale and the Ashcroft scale,the positive staining of collagen Ⅰ(COL Ⅰ)and COL Ⅲ was detected using immunohistochemistry;the protein expression of transforming growth factor-β1(TGF-β1),fibronectin(FN),andα-smooth muscle actin(α-SMA)were measured by Western blotting.The rat serum samples were further screened for differential metabolites using ultra performance liquid chromatographytandem quadrupole time of flight mass spectrometr(UPLC-Q-TOF-MS)and pathway analysis was performed based on MetaboAnalyst 5.0.Results Compared with those in the normal control group,pathological changes such as alveolar structure destruction,the fibrous nodules encapsulated SiO2 particles were increased in lung tissues of rats in model group,alveolitis score and pulmonary fibrosis score were significantly higher(alveolitis score:2.62±0.27 vs.0.20±0.15,pulmonary fibrosis score:5.42±0.66 vs.0.50±0.84,both P<0.01);pulmonary function index including Cydn,FVC,and TV were significantly decreased[Cdyn(mL/cmH2O):0.26±0.03 vs.0.33±0.03,FVC(mL):8.09±0.47 vs.10.99±0.38,TV(mL):1.95±0.19 vs.2.53±0.26,all P<0.01];positive staining of COL Ⅰ,COL Ⅲ and ɑ-SMA,FN,TGF-β1 proteins expression showed higher in lung tissues[positive staining of COL Ⅰ(A value):13.47±1.76 vs.5.77±0.45;positive staining of COL Ⅲ(A value):10.39±0.47 vs.6.19±0.77,FN protein expression(FN/GAPDH):0.33±0.02 vs.0.21±0.07,α-SMA protein expression(α-SMA/GAPDH):1.78±0.16 vs.1.11±0.24,TGF-β1 protein expression(TGF-β1/GAPDH):0.52±0.10 vs.0.11±0.46,all P<0.01].Compared with the model group,the pathological changes of lung tissues were almost restored,alveolitis score and lung fibrosis score were significantly reduced in JCF and Tetrandrine groups(alveolitis score:1.10±0.15,1.33±0.31 vs.2.62±0.27,pulmonary fibrosis score:3.50±0.45,4.33±0.98 vs.5.42±0.66,all P<0.01);the pulmonary function index Cydn,FVC and TV were significantly increased[Cdyn(mL/cmH2O):0.32±0.05,0.31±0.04 vs.0.26±0.03,FVC(mL):9.41±0.85,8.70±0.92 vs.8.09±0.47,TV(mL):2.70±0.19,2.27±0.15 vs.1.95±0.19,all P<0.05];positive staining of COL Ⅰ,COL Ⅲ,and protein expression of FN,ɑ-SMA,and TGF-β1 in lung tissues was significantly decreased[COL Ⅰ(A value):7.09±0.67,8.13±0.64 vs.13.47±1.76,COL Ⅲ(A value):8.19±0.66,8.52±0.22 vs.10.39±0.47,FN protein expression(FN/GAPDH):0.19±0.06,0.24±0.03 vs.0.33±0.02,α-SMA protein expression(α-SMA/GAPDH):0.89±0.41,0.88±0.08 vs.1.78±0.16,TGF-β1 protein expression(TGF-β1/GAPDH):0.04±0.03,0.06±0.01 vs.0.52±0.10,all P<0.05].Metabolomics analysis showed that a total of 10 major differential metabolites were identified between normal control group,model group and JCF group,including arachidonic acid,palmitic acid,indole-3-acetic acid,propionylcarnitine,(S)-4-hydroxymandelonitrile,nalidixic acid,benzocaine,gramine,4-ethylphenol,N-benzylfor mamide.The differential metabolites in silicosis rats reversed by JCF treatment were mainly enriched,including unsaturated fatty acid biosynthesis,arachidonic acid metabolism,tryptophan metabolism,fatty acid elongation,fatty acid degradation and biosynthesis.Conclusion JCF could effectively improve the silicosis fibrosis,which is mainly related to biosynthesis of unsaturated fatty acids biosynthesis,arachidonic acid metabolism,tryptophan metabolism,fatty acid elongation,fatty acid degradation and biosynthesis.