Macrophage WTAP Deficiency Protects Atherosclerosis by Improving Macrophage Apoptosis in an m 6 A‐Independent Manner

ABSTRACT Wilms' tumor 1‐associating protein (WTAP), a core component of the N6‐methyladenosine (m 6 A) methyltransferase complex, plays a crucial role in various biological processes. However, functional studies of WTAP in atherosclerosis development are largely unknown. Here, we demonstrate that WTAP expression was elevated in lipopolysaccharide (LPS)‐stimulated macrophages and atherosclerotic lesions of apolipoprotein E‐deficient ( ApoE −/− ) mice. To explore its functional role, we employed AAV8‐mediated in vivo knockdown and siRNA‐mediated in vitro silencing, which revealed that WTAP deficiency attenuated macrophage apoptosis and reduced atherosclerotic plaque formation. Mechanistically, we identified myosin heavy chain 11 (MYH11) as a mediator of WTAP‐induced macrophage apoptosis. Notably, WTAP upregulated MYH11 expression in macrophages through an m 6 A‐independent mechanism. These results delineate a new molecular paradigm that macrophage WTAP promotes macrophage apoptosis and atherosclerosis by increasing MYH11 expression, indicating that WTAP may be a potential therapeutic target against atherosclerosis.