Ligustrazine alleviates cyclophosphamide-induced hepatotoxicity via the inhibition of Txnip/Trx/NF-κB pathway

Cyclophosphamide (CP) is a common therapeutic drug for cancer, but exposure to CP can cause acute hepatotoxicity. This study aimed to elucidate the protective effects of Ligustrazine (2, 3, 5, 6-tetramethylpyrazine, TMP) on hepatotoxicity induced by CP or its active metabolite 4-hydroperoxycyclophosphamide (4-HC). We presented a comprehensive investigation about the hepatoprotection of TMP on CP-induced mice and 4-HC-treated HSC-LX2 cells. Liver function was detected via enzyme-linked immunosorbent assay (ELISA). Hepatic histopathology analysis was performed via hematoxylin and eosin (H&E) and Masson staining. Survival of hepatocytes was detected by TUNEL assay. Related proteins in the thioredoxin (Trx)-interacting protein (Txnip)/Trx/Nuclear factor-kappa B (NF-κB) pathway were measured by western blotting. The results indicated that CP or 4-HC could increase the levels of alanine aminotransferase and aspartate aminotransferase, enhance inflammatory factors and oxidative indicators, and suppress the activity of oxidoreductases. Moreover, significant changes in liver histological structure, fibrosis, and cell death were observed through the activation of Txnip/Trx/NF-κB pathway. In contrast, administration of TMP significantly reversed these above changes. Furthermore, TMP intervention participated in the inhibition of NLRP3 inflammasome accompanied with pyroptosis, as well as upregulating Trx expression and downregulating p-NF-κB, while the protective effect of TMP was limited to the involvement of Txnip overexpression. TMP treatment could significantly alleviate the hepatotoxicity process as evidenced by improving the structure and function of the liver, inhibiting oxidative stress and inflammation accompanied with pyroptosis, which was positively correlated with the inhibition of Txnip/Trx/NF-κB pathway.