TMEM41B Contributes to Atherosclerosis by Promoting Lipid Synthesis in Vascular Smooth Muscle Cells via Fatty Acid Synthase Stabilization

Abstract

Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. VSMCs specific silencing TMEM41B expression in apolipoprotein E-deficient (ApoE-/-) mice markedly reduced plaque size and macrophage infiltration. Overexpressing TMEM41B in cultured VSMCs alters intracellular lipid profiles through stabilizing fatty acid synthase (FASN), a crucial enzyme in fatty acids synthesis, via inhibiting its ubiquitination and degradation. The TMEM41B/FASN axis drives lipid synthesis, promotes intracellular lipid storage, and facilitates the release of pro-inflammatory cytokines. Further, herpes simplex virus (HSV) infection amplified TMEM41B expression via OCT-1-mediated transcriptional activation, linking viral infection to lipid metabolic reprogramming in AS. These findings redefine the paradigm of VSMC-derived foam cell formation and suggest that targeting the TMEM41B/FASN axis could offer a transformative therapeutic strategy for AS, particularly in patients with HSV infection.