Lycorine ameliorates liver steatosis, oxidative stress, ferroptosis and intestinal homeostasis imbalance in MASLD mice.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide and few drugs are available for its treatment. Lycorine has effective anti-inflammatory and lipid-lowering effects, but the impact on MASLD is not fully understood. In this study, we intend to test the intervention effect of lycorine on MASLD. METHODS: A MASLD mouse model was constructed on a high-fat diet for 16 weeks, and low, medium, and high doses of lycorine were given by gavage for the last 4 weeks. Detecting indicators related to liver steatosis, oxidative stress, and ferroptosis. In vivo and in vitro experiments co-validate potential targets identified by network pharmacology, molecular docking and western blot for lycorine intervention in MASLD liver. A combination of pathology, western blot, qRT-PCR, and 16 S rRNA sequencing verified adipose tissue and intestinal alterations. RESULTS: Lycorine ameliorated hepatic steatosis, oxidative stress and ferroptosis in MASLD mice by inhibiting the expression of phosphorylated EGFR, inhibiting the PI3K/AKT signaling pathway. We also observed a dose-dependent effect of lycorine to improve some of the indicators of MASLD. In vitro, knockdown of EGFR significantly attenuated palmitic acid-induced hepatocyte steatosis. In addition, lycorine promoted WAT browning for thermogenesis and energy consumption, affected the composition of intestinal flora, improved the intestinal barrier, and reduced intestinal inflammation. CONCLUSIONS: EGFR was the target of lycorine intervention in MASLD. Lycorine ameliorated hepatic steatosis, oxidative stress and ferroptosis by affecting the EGFR/PI3K/AKT signaling pathway in MASLD mice. Furthermore, lycorine promoted WAT browning and ameliorated intestinal homeostatic imbalance. The above effects may also have dose-dependent effects.