FABP4 Disrupts Redox Homeostasis Through GOT2 Interaction to Drive Macrophage Mitochondrial Lipid Metabolic...

This study aims to investigate the role of fatty acid-binding protein 4 (FABP4) in macrophage lipid metabolism and inflammatory responses during atherosclerosis development, and to determine whether its function is mediated through interaction with glutamate oxaloacetate transaminase 2 (GOT2). Herein, macrophage-specific FABP4 knockout mice and RAW 264.7 macrophages were subjected to high-fat diet (HFD) or oxidized LDL (ox-LDL) treatment, respectively. Co-immunoprecipitation (Co-IP), qPCR, western blot, flow cytometry, ELISA, enzymatic assays, and histological staining (hematoxylin and eosin (H&E), Oil Red O) were used to assess protein interaction, expression, cytokine secretion, lipid accumulation, pro-inflammatory activation, and redox state. Macrophage-specific FABP4 deletion markedly reduced atherosclerotic plaque formation, lipid accumulation, pro-inflammatory cytokine levels, and the proportion of CD86⁺ pro-inflammatory macrophages, while improving systemic lipid profiles. Mechanistically, FABP4 directly bound to mitochondrial GOT2 without altering its expression, leading to disruption of mitochondrial NADH/NAD⁺ redox homeostasis and subsequent metabolic dysfunction. Importantly, concurrent knockdown of GOT2 fully reversed the beneficial effects of FABP4 deficiency on lipid metabolism and inflammation, confirming GOT2 as a critical downstream mediator. FABP4 promotes atherosclerosis by binding to GOT2 and disrupting mitochondrial redox balance, thereby driving macrophage lipid metabolic reprogramming and inflammatory activation. Targeting the FABP4-GOT2 axis may offer a novel therapeutic strategy for atherosclerosis and related metabolic diseases.