Background Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver (NAFL), and Forkhead box O1 (FoxO1) plays an important role in hepatic lipid metabolism. In this study, we aimed to examine the role and mechanisms of the FoxO1 inhibitor AS1842856 (AS) in NASH mice.

Methods Mice were given methionine-choline-sufficient (MCS) or methionine and choline-deficient (MCD) diet for 5 weeks, respectively, along with AS (60 mg/kg) or vehicle gavage treatment (0.2 mL/mouse/day) (IDDF2024-ABS-0115 Figure 1 (A)).

Results Compared to the MCD group of mice, AS exhibited the following effects in NASH mice: attenuation of liver weight/body weight (IDDF2024-ABS-0115 Figure 1 (B)), reduction in serum triglyceride (TG) levels (IDDF2024-ABS-0115 Figure 1 (C)), mitigation of hepatic steatosis (IDDF2024-ABS-0115 Figure 1 (D,E)). Furthermore, AS altered the composition of gut microbiota in NASH mice (IDDF2024-ABS-0115 Figure 1 (F)), resulting in an increase in beneficial bacteria such as Akkermansia_muciniphila, Parabacteroides_distasonis, and Lacrimispora celerecrescens (IDDF2024-ABS-0115 Figure 1 (G)), which are associated with metabolic functions.

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Abstract IDDF2024-ABS-0115 Figure 1

Conclusions The FoxO1 inhibitor AS can ameliorate hepatic steatosis and intestinal dysbiosis in NASH mice, making it a promising candidate for the treatment of NASH.