Long-term abuse of methamphetamine (MA) can cause lung toxicity. Intercellular communication between macrophages and alveolar epithelial cells (AECs) is critical for maintaining lung homeostasis. Microvesicles (MVs) are important medium of intercellular communication. However, the mechanism of macrophage microvesicles (MMVs) in MA-induced chronic lung injury remains unclear. This study is aimed to investigate if MA can augment the activity of MMVs, if circ_YTHDF2 is a key factor in MMVs-mediated macrophages-AECs communication, and is to explore the mechanism of MMVs-derived circ_YTHDF2 in MA-induced chronic lung injury. MA elevated PV and nPAT, reduced the number of alveolar sacs, and thickened the alveolar septum. MA accelerated the release of MMVs and the uptake of MMVs by AECs. Circ_YTHDF2 was down-regulated in lung and MMVs induced by MA. The immune factors in MMVs were increased by si-circ_YTHDF. Circ_YTHDF2 knockdown in MMVs induced inflammation and remodeling in the internalized AECs by MMVs, which was reversed by circ_YTHDF2 overexpression in MMVs. Circ_YTHDF2 bounded specifically to and sponged miRNA-145-5p. RUNX3 was identified as potential target of miR-145-5p. RUNX3 targeted ZEB1-related inflammation and EMT of AECs. In vivo, circ_YTHDF2 overexpression-MMVs attenuated MA-induced lung inflammation and remodeling by circ_YTHDF2/miRNA-145-5p/RUNX3 axis. Therefore, MA abuse can induce pulmonary dysfunction and alveoli injury. The immunoactivity of MMVs is regulated by circ_YTHDF2. Circ_YTHDF2 in MMVs is the key to the communication between macrophages and AECs. Circ_YTHDF2 sponges miR-145-5p targeting RUNX3 to participate in ZEB1-related inflammation and remodeling of AECs. MMVs-derived circ_YTHDF2 would be an important therapeutic target for MA-induced chronic lung injury. KEY POINTS: Methamphetamine (MA) abuse induces pulmonary dysfunction and alveoli injury. The immunoactivity of macrophage microvesicles (MMVs) is regulated by circ_YTHDF2. Circ_YTHDF2 in MMVs is the key to MMV-mediated the intercellular communication between macrophages and alveolar epithelial cells. Circ_YTHDF2 sponges miR-145-5p targeting RUNX3 to participate in ZEB1-related inflammation and remodeling. MMVs-derived circ_YTHDF2 would be an important therapeutic target for MA-induced chronic lung injury. Abstract figure legend MA abuse induced lung dysfunction and alveoli injury, and augmented the release of MMVs, and circ-YTHDF2 sponges miR-145-5p targeting RUNX3 to participate in ZEB1-related inflammation and EMT of AECs. MMVs-derived circ-YTHDF2 is the key factor in the communication between macrophages and AECs, and is involved in MA-induced lung injury. Figure was created with BioRender.com. This article is protected by copyright. All rights reserved.