Aim To explore the potential effects of acid sphingomyelinase (aSMase) and its sphingomyelin hydrolysate ceramide (Cer) on silica induced pulmonary fibrosis. Methods The expression of key enzymes and metabolites in the aSMase/Cer signaling pathway were tested in omics analysis, silica induced mice model and in vitro as well. The exogenous CER, the high expression of SMPD1 which encodes aSMase or transfected with lentivirus-mediated high expression of SMPD1 were given in vivo or in vitro respectively. Results The levels of sphingomyelin, aSMase and Cer in silica-induced silicosis were lower than those in controls. Meanwhile, the levels of aSMase and Cer in NIH-3T3 cells after TGF-?1 stimulation were also decreased. Phagocytosis of silica particles by macrophages promoted lung fibroblast transdifferentiation and activated aSMase/Cer pathway. In addition, the collagen content in silicotic nodules and the numbers of large nodule were reduced by exogenous Cer or by adeno-associated virus-mediated high expression of SMPD1 in vivo. Meanwhile, the level of fibrotic genes in TGF-?1-induced lung fibroblasts activation was reduced when given Cer and high expression of SMPD1. After exogenous Cer or SMPD1 overexpression, the proliferation, and migration ability of NIH-3T3 were decreased, while apoptosis was increased. Conclusions aSMase and Cer were downregulated in silica-induced lung fibrosis. Exogenous Cer or SMPD1 high expression can alleviate silica-induced pulmonary fibrosis. (Sponsored by National Natural Science Foundation of China, 81970061)