Chelerythrine Protects Against Acetaminophen-Induced Acute Liver Injury: Insights from Gut Microbiota and Multi-Omics Analysis

Chelerythrine (CHE) is the main active component of <i>Chelidonium majus</i> L., possessing excellent antioxidant and anti-inflammatory properties. However, the protective effects of CHE against liver injury and its underlying mechanisms remain unclear. We aimed to investigate the effects of CHE on acute liver injury (ALI) and explore its underlying mechanisms. Mice were orally administered with or without CHE (15 and 30 mg/kg) treatment for 7 days, followed by a single intraperitoneal injection of acetaminophen (APAP, 350 mg/kg). After 24 h, serum, liver, and fecal samples were collected. Then, 16S rRNA gene sequencing, metabolomics, and transcriptomics approaches were employed to investigate the protective effects of CHE against ALI. Finally, we elucidated the role of CHE in restoring gut microbiota and metabolic disorders in the context of ALI. The results showed that CHE significantly inhibited ALT and AST levels (<i>p</i> < 0.001). Furthermore, CHE counteracted APAP-induced alterations in IL-6, IL-1β, TNF-α, MPO, MDA, H₂O₂, CAT, SOD, and GSH (<i>p</i> < 0.05). These results indicate that CHE possesses antioxidant properties and inhibits inflammatory factors, thereby protecting the organism from APAP-induced ALI. CHE treatment significantly altered gut microbiota composition, particularly increasing levels of the beneficial bacterium <i>Barnesiella intestinihominis</i> (<i>p</i> < 0.05). In addition, CHE reversed metabolic disturbances and inhibited oxidative and inflammatory signaling pathways. These findings suggest that CHE is a natural hepatoprotective agent that prevents ALI by modulating gut microbiota, related metabolites, oxidative stress, and inflammation. This study provides new insights into CHE as a potential therapeutic approach for ALI.