Protective effect of liquiritin against cisplatin-induced liver injury in mice through reduction of inflammation, oxidative stress, apoptosis and inhibition of p38 MAPK/p53 pathway based on network pharmacology and in experimental validation.

Ethnopharmacological Relevance: Cisplatin is widely used in chemotherapy, but hepatotoxicity limits its effectiveness. Liquiritin has liver-protective effects, but its mechanisms have not been elucidated in combination with cisplatin for liver-injury treatment in mice.

Aim Of The Study: This investigation explored liquiritin's protective effect against cisplatin-induced liver damage in mice and its mechanisms.

Materials And Methods: Liquiritin's targets and mechanisms were investigated using pharmacological methods. Targets related to liquiritin and hepatotoxicity were identified using online databases, followed by cross-target and mechanism extraction using STRING, Cytoscape, and DAVID databases. 60 Kunming mice in five groups (n = 12) received physiological saline (control group), cisplatin (5 mg/kg), liquiritin (40 mg/kg), liquiritin (20 mg/kg) with cisplatin (5 mg/kg), and liquiritin (40 mg/kg) with cisplatin (5 mg/kg). Mice received oral liquiritin daily for 7 days. Cisplatin was injected intraperitoneally on days 3 and 6. We evaluated liquiritin's effects on liver coefficients, liver-function indices (ALT, AST, ALP), oxidative-stress indices (CAT, SOD, CAT, and GSH), and inflammatory-factor levels (TNF-α and IL-6). Pathological changes were observed with H&E and Masson-trichrome staining, apoptosis was observed with TUNEL staining, and apoptosis-related proteins and the p38 MAPK/p53 pathway were analysed with western blot.

Results: 99 targets and 38 pathways were involved in the liquiritin-target pathway network. Liquiritin's key targets included caspase3, Bcl-2, and MAPK1, and it might regulate the MAPK signaling pathway. In vivo validation results, liquiritin had significantly lower liver coefficients. ALT, AST, ALP, MDA, TNF-α, and IL-6 were significantly decreased after liquiritin treatment, while SOD, CAT, and GSH were increased considerably. Liquiritin upregulated Bcl-2 protein expression and suppressed Bax, Caspase-3, c-Caspase-3 and PUMA protein expression, and the p38 MAPK/p53 pathway.

Conclusions: Liquiritin exerts hepatoprotective effects by modulating the p38 MAPK/p53 pathway, thereby reducing inflammation, oxidative stress, and apoptosis.