The study’s principal findings are that: (1) mir-21 mediates collagen synthesis by activating the ERK/NF-κB/NLRP3 inflammsome pathway via targeting Spry1 in lung fibroblasts; (2) mir-21 is up-regulated in primary lung fibroblasts treated with AngII and in BLM-induced pulmonary fibrosis; and (3) mir-21 mediates the inhibitory effect of ACE2/Ang(1–7) on AngII-induced NLRP3 inflammasome activation by targeting Spry1 in lung fibroblasts. Here, SPRY1 is linked to pulmonary fibrosis.