Bardoxolone methyl prevents metabolic dysfunction‐associated steatohepatitis by inhibiting macrophage infiltration

Abstract Background and Purpose Bardoxolone methyl (2‐cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oic acid methyl ester, CDDO‐Me) is a potent activator of nuclear factor erythroid 2‐related factor 2 (Nrf2), which induces the expression of antioxidative‐associated genes. CDDO‐Me exerts protective effects against chronic inflammatory diseases in the kidneys and lungs. However, its pharmacological effects on metabolic dysfunction‐associated steatohepatitis (MASH) caused by fat accumulation remain unknown. In this study, we examined the hepatoprotective effects of CDDO‐Me in a diet‐induced MASH mouse model and elucidated its pharmacological mechanisms using RNA‐seq analysis. Experimental Approach CDDO‐Me was orally administered to mice fed a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD), and histological, biochemical, and transcriptomic analyses were performed on livers of mice that developed MASH. Key results CDDO‐Me administration induced the expression of antioxidant genes and cholesterol transporters downstream of Nrf2 and significantly prevented the symptoms of MASH. Whole‐transcriptome analysis revealed that CDDO‐Me inhibited the inflammatory pathway that led to phagocyte recruitment, in addition to activating the Nrf2‐dependent pathway. Among inflammatory pathways, CC chemokine ligands (CCL)3 and CCL4, which are downstream of NF‐κB and are associated with the recruitment of macrophages expressing CC chemokine receptors (CCR)1 and CCR5, were released into the blood in MASH mice. However, CDDO‐Me directly inhibited the expression of CCL3‐CCR1 and CCL4‐CCR5 in macrophages. Conclusions and Implications Overall, we revealed the potent hepatoprotective effect of CDDO‐Me in a MASH mouse model and demonstrated that its pharmacological effects were closely associated with a reduction of macrophage infiltration, through CCL3‐CCR1 and CCL4‐CCR5 inhibition, in addition to Nrf2‐mediated hepatoprotective effects.