<p>Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of foam cells within the arterial wall. Despite substantial progress, the molecular mechanisms governing foam cell formation remain incompletely understood. Here, we identify fibronectin leucine-rich transmembrane protein 2 (FLRT2) as a previously unrecognized regulator of macrophage-driven atherogenesis through the facilitation of foam cell formation. FLRT2 expression was markedly elevated in macrophages within both murine and human atherosclerotic plaques. Functionally, adenovirus-mediated FLRT2 overexpression aggravated atherosclerotic lesion development in <i>Apoe</i>^−/− mice, whereas macrophage-specific <i>Flrt2</i> deletion significantly reduced the plaque burden in both AAV8-PCSK9-injected and <i>Apoe</i>^−/− atherosclerotic models. Mechanistically, the loss of <i>Flrt2</i> attenuated local inflammatory responses, as indicated by lower proportions of proinflammatory Ly6C^hi monocytes in the peritoneal cavity and bone marrow and fewer M1 macrophages in the spleen. Furthermore, FLRT2 promoted foam cell formation by suppressing the cholesterol efflux transporter ABCA1 at the post-transcriptional level. We demonstrate that FLRT2 enhances ABCA1 ubiquitin‒proteasome degradation by inhibiting USP22-mediated deubiquitination. Collectively, our findings identify FLRT2 as a key regulator of macrophage lipid metabolism and inflammation, revealing a novel FLRT2–USP22–ABCA1 axis that promotes foam cell formation and accelerates atherosclerosis. Therefore, targeting FLRT2 may represent a promising therapeutic strategy for atherosclerotic cardiovascular disease.</p>