on in chronic heart failure, despite similar lowering of plasma UA levels^[@CR31]^. That study also showed that the mechanism of action of allopurinol, with respect to its improvement of endothelial function, lies in its ability to abolish XO-mediated vascular oxidative stress rather than reducing UA.

Febuxostat reduced the infiltration and activation of liver macrophages, resulting in the attenuation of hepatic inflammation in CL diet-fed mice. Hepatic inflammation mediated by macrophage/monocyte-derived proinflammatory cytokines promotes lipogenesis by inducing insulin resistance^[@CR32]^. In fact, the depletion of liver macrophages by liposomal clodronate ameliorates hepatic steatosis and insulin sensitivity in mice fed a high-fat diet^[@CR33]^. Furthermore, specific ablation of M1-like macrophages restores insulin sensitivity in diet-induced obese mice^[@CR34]^. Additionally, M2-like liver macrophages have been reported to mitigate NAFLD by promoting apoptosis of M1-like macrophages^[@CR35]^. Therefore, the decreased number of hepatic macrophages and their M2-dominant polarization account, at least in part, for the attenuation of insulin resistance and steatohepatitis in febuxostat-treated CL diet-fed mice, even though the mRNA expression of Nlrp3 or Il-1β in the liver is not decreased. However, we do not exclude the possibility that the effects of XO inhibitors on CL diet-induced NAFLD are mediated by NLRP3 inflammasome-dependent mechanisms, since the efficacy and mechanism of action of XO inhibitors against NAFLD might be dependent on the dietary model. This point warrants further investigations.

Finally, our clinical study demonstrated that febuxostat has the potential to reduce liver damage in NAFLD. Febuxostat, with its non-purine structure, selectively inhibits both the oxidized and reduced form of XO^[@CR36],[@CR37]^. In contrast, allopurinol and its oxidized active metabolite, oxypurinol, inhibit only the oxidized form of XO, but also inhibit enzymes involved in purine and pyrimidine metabolism, si