Asiatic acid ameliorates rifampicin- and isoniazid-induced liver injury in vivo by regulating sphingolipid metabolism and mitogen-activated protein kinase signalling pathways

In this study, we aimed to determine whether asiatic acid (AA) exerts any therapeutic effects on rifampicin (RFP)- and isoniazid (INH)-induced liver injury and elucidate the underlying mechanisms. Briefly, liver injury in mice was induced via RFP and INH administration. We investigated the effects and potential action mechanisms of AA on liver injury using transcriptomics, metabolomics and various examinations. We found that AA significantly ameliorated the pathological changes in liver tissues and decreased the transaminase activity, inflammation and oxidative stress damage. Transcriptomics revealed 147 differentially expressed genes (DEGs) between the AA and model groups that were enriched in metabolic and mitogen-activated protein kinase (MAPK) signalling pathways. Metabolomics revealed 778 differentially expressed metabolites between the AA and model groups. Furthermore, integrated transcriptomics and metabolomics analyses revealed strong correlations between DEGs and differentially expressed metabolites and indicated that AA regulates the sphingolipid metabolism by inhibiting the expression of delta 4-desaturase, sphingolipid 1. Experimental results confirmed that AA inhibited the MAPK signalling pathway. In summary, AA inhibits inflammation and oxidative stress damage by regulating the sphingolipid metabolism pathway and blocking the MAPK signalling pathway, thereby relieving the RFP/INH-induced liver injury.

Automated summary

This study aimed to investigate the therapeutic effects of asiatic acid (AA) on rifampicin (RFP)- and isoniazid (INH)-induced liver injury and understand the mechanisms involved. AA significantly improved liver tissue pathology, decreased transaminase activity, inflammation, and oxidative stress damage. Transcriptomics and metabolomics analyses revealed differentially expressed genes and metabolites between the AA and model groups, highlighting the importance of sphingolipid metabolism and the MAPK signaling pathway. Experimental results confirmed that AA inhibited the MAPK signaling pathway. In conclusion, AA alleviates RFP/INH-induced liver injury by modulating sphingolipid metabolism and blocking the MAPK signaling pathway.