Monocyte-derived macrophages (MoMacs) are the most important effector cells that cause pulmonary fibrosis. However, the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the progression of pulmonary fibrosis remain unclear. Integration of single-cell and spatial transcriptomic analyses revealed that the silicosis niche was occupied by a subset of MoMacs, identified as Spp1Macs, which remain in an immature transitional state of differentiation during silicosis. This study investigated the mechanistic foundations of mitochondrial damage induced by the lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by Pla2g7)-acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1)-cardiolipin (CL) signaling pathway, which interferes with Spp1Mac differentiation. We demonstrated that in SiO-induced MoMacs, Lp-PLA2 induces abnormal CL acylation through the activation of ALCAT1, resulting in impaired mitochondrial localization of PINK1 and LC3B and mitochondrial autophagy defects. Simultaneously, lysosomal dysfunction causes the release of the lysosomal protein cathepsin B into the cytoplasm, which involves M1 and M2 macrophage polarization and the activation of proinflammatory and profibrotic pathways. Furthermore, we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model. Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals.