The Chinese herbal KangXianYiAi formula inhibits hepatocellular carcinoma by reducing glutathione and inducing ferroptosis

Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and has a moderate treatment outcome. The traditional Chinese medicine KangXianYiAi formula (KXYA) has shown a clinically therapeutic effect on liver lesions. Here, we aimed to explore the effect and mechanism of KXYA in treating HCC.
Methods: The rat HCC model induced with diethylnitrosamine was treated with KXYA. After treatment, the rat's serum and the liver tissues were used to detect biochemical indices and perform pathological examinations, second-generation sequencing (RNA-seq), and phosphoproteomics analysis (PPOA). The hepatoma cells were treated with KXYA in vitro and a nude-mice model. The expression levels of genes were detected by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), Western blotting (WB), and immunohistochemistry approaches. The expression and prognosis data of genes in HCC were obtained from the public database.
Results: Compared to the model, KXYA treatment significantly downregulated the rats’ serum hepatitis index, inflammatory damage, collagen deposition, and malignant proliferation of hepatocytes. And through the RNA-seq and PPOA analysis of rat liver tissues, we obtained the key pathways of KXYA including glutathione metabolism and ferroptosis. The qRT-PCR and WB results suggested that the key targets of UGDH, AKR1B10, and SLC7A11 were abnormally upregulated in HCC and downregulated to normal levels after KXYA treatment. In the public database, UGDH, AKR1B10, and SLC7A11 expression was significantly upregulated in HCC and indicated a poor prognosis.
Discussion: Our study showed that KXYA treatment could effectively inhibit the progression of HCC by reducing glutathione and inducing ferroptosis of liver cancer cells.