Targeting FABP4 in treating atherosclerosis and metabolic disorders: from mechanism to therapies

Abstract

Fatty acid-binding protein 4 (FABP4), initially characterized as an intracellular lipid chaperone in adipocytes and macrophages, is now recognized as a pleiotropic regulator of atherosclerosis, mediating pro-atherogenic effects across various vascular cell types. In adipocytes, FABP4 is regulated by a PPARγ-driven positive loop and suppressed by AMPK-linked lipolysis feedback, promoting systemic lipotoxicity and acting as an endocrine factor on vascular cells. In macrophages, atherogenic stimuli (e.g., ox-LDL, palmitate) upregulate FABP4 via NF-κB and JAK/STAT2, impairing cholesterol efflux (PPARγ-LXRα-ABCA1) and activating JNK/NF-κB and NLRP3 inflammasome to exacerbate inflammation and foam cell formation. In endothelial cells, FABP4 was internalized via CK1 and initiates an “uptake–induction” loop driving vascular injury. In VSMCs, FABP4, upregulated by arterial injury, promotes proliferation, migration, and vascular remodeling, consolidating its role in atherogenesis. This review systematically synthesizes the expression and regulation of FABP4 across four cell types and their differential contributions to atherosclerosis. Given that FABP4 resides at the critical nexus of metabolic dysfunction and vascular inflammation, targeting this molecule represents a highly promising therapeutic frontier. We also systematically summarize current pharmacological intervention strategies, focusing on preclinical small molecule inhibitors, naturally occurring bioactive compounds, and innovative monoclonal neutralizing antibodies designed to block pathogenic extracellular FABP4 signaling. Collectively, interrupting cell-specific actions of FABP4 or its intercellular communication network offers a novel, multi-pronged therapeutic paradigm for atherosclerotic cardiovascular disease.