Macrophage WTAP Deficiency Protects Atherosclerosis by Improving Macrophage Apoptosis in an m6A-Independent Manner

Wilms' tumor 1-associating protein (WTAP), a core component of the N6-methyladenosine (m⁶A) 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 m⁶A-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.