FABP4 Disrupts Redox Homeostasis Through GOT2 Interaction to Drive Macrophage Mitochondrial Lipid Metabolic Reprogramming in Atherosclerosis

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.