Melatonin relieves liver fibrosis induced by Txnrd3 knockdown and nickel exposure via IRE1/NF-kB/NLRP3 and PERK/TGF-β1 axis activation

Nickel(Ni) accumulates in the environment due to human activities such as electroplating, alloy production, stainless steel, Ni‑cadmium batteries and industrial production. Ni enriched in humans and animals through food chains, poses a serious health threat. Txnrd3, as a member of the thioredoxin reductase family, has long been thought to be testicular specific and involved in sperm maturation. However, its role in liver diseases still unknown. Melatonin exerts its antioxidant effects directly through its ability to clear free radicals and protects the liver from oxidative damage. Hepatic fibrosis with an ever-increasing incidence year by year, is correlating with outcome and risk of hepatocellular carcinoma.In this study, 60 8-week-old male C57BL/6 wild-type mice and 60 Txnrd3-/- mice were randomly divided into three groups, respectively. Control group was gavaged with distilled water, 10 mg/kg NiCl2 in Ni group, Ni + Mel group treated with 2 mg/kg melatonin in the morning, 10 mg/kg NiCl2 in the afternoon, serum and tissue was extracted after 21 days.Results showed that liver function was significantly worse after Ni exposure, morphological and masson staining showed more significant liver fibrosis in Txnrd3-/- mice, damage of organelles in hepatocytes was observed. qPCR and WB results showed activation of the IRE1/Nuclear factor-kappa B/NLRP3 axis during Ni exposure lead to hepatocyte pyroptosis, while upregulation of PERK/TGF-β promoted liver fibrosis process and Txnrd3 knockout exacerbated liver damage during Ni exposure.The above results will lay the theoretical foundation for the monitoring and clinical treatment of Ni exposure.