FASEB J. 2026 Jul 15;40(13):e72105. doi: 10.1096/fj.202501525RR.
ABSTRACT
Macrophage foam cell formation is the mark of atherosclerosis (AS). Krüppel-like factor (KLF)11 prevented the development of AS in diabetic conditions. However, it is not clear whether KLF11 inhibits macrophage foam cell formation. High-fat diet (HFD) was administered to ApoE-/- mice to build an in vivo AS model. An adeno-associated virus (AAV) vector incorporating the macrophage-specific promoter CD68 was utilized to construct the macrophage-specific KLF11 overexpression mouse model. Treatment of RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) elicited foam cell formation. Dual luciferase reporter gene assays, ChIP, and RIP were applied to detect interactions between molecules. Pathological changes in arterial tissue were detected by HE staining, and the area of collagenous fibers was measured by Masson staining. Cholesterol efflux and cholesterol uptake were analyzed using NBD-cholesterol and Dil-ox-LDL methods, respectively. Lipid and inflammation levels were assessed using commercially available kits. Adipogenesis was assayed via Oil red O staining. KLF11 expression was downregulated, and overexpression of KLF11 suppressed inflammation, cholesterol levels, and lipid accumulation in AS. Meanwhile, overexpression of KLF11 inhibited ox-LDL-induced foam cell formation. Mechanistically, IGF2BP3 promoted KLF11 stabilization and expression in an m6A-dependent manner, and KLF11 transcriptionally inhibited ATP5B, which prevented NLRP3 inflammasome activation. IGF2BP3 mediated KLF11 stabilization to inhibit macrophage foam cell formation and alleviate AS through transcriptional inhibition of ATP5B to block NLRP3 inflammasome activation.
PMID:42384007 | DOI:10.1096/fj.202501525RR