Magnolin ameliorates acetaminophen-induced liver injury in mice via modulating the MAPK pathway and lipid metabolism

Acetaminophen (APAP)-induced liver injury (AILI) represents a common yet potentially severe type of drug-induced liver injury with limited available effective therapeutic methods. Magnolin possesses excellent anti-inflammatory and antioxidant properties for treating various diseases. However, its effects against AILI and the fundamental mechanisms still lack comprehensive exploration. This research endeavors to assess magnolin's hepatoprotective properties against AILI. The AILI model was established in male C57BL/6 mice via intraperitoneal injection of 300 mg/kg APAP and in the HepG2 cell line by treating it with 20 mM APAP. The levels of oxidation, liver damage and inflammation were assessed. Transcriptomics and metabolomics were utilized to explore the mechanism underlying magnolin treatment in AILI. We found that 5 mg/kg magnolin effectively mitigated the elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), along with inflammatory factor (IL-6, and TNF-α) levels in vivo. Meanwhile, magnolin relieved oxidative stress by increasing superoxide dismutase activity and reducing malondialdehyde along with oxidized glutathione/reduced glutathione (GSSG/GSH). 6 μM magnolin increased cell viability and reduced the lipid peroxidation in vitro. Furthermore, 5 mg/kg magnolin altered the expression of 413 genes and the levels of 70 metabolites compared with Control group, which were enriched in lipid metabolism, inflammatory responses, and the MAPK signaling pathway. However, 10 mg/kg magnolin tended to exacerbate liver damage. Overall, 5 mg/kg magnolin effectively protects against AILI by modulating inflammatory responses and the MAPK pathway, whereas 10 mg/kg worsens liver injury, underscoring the need for dose optimization. These findings offer a fresh perspective and novel therapy for AILI.