Transcriptional regulation of ATOX1 by PRRX2 impacts the progression and cuproptosis of hepatocellular carcinoma.

The copper chaperone antioxidant 1 (ATOX1) has been identified as a potential oncogene in certain types of cancer, and its increased expression is associated with poor prognoses. Nevertheless, its function in hepatocellular carcinoma (HCC) remains largely uninvestigated. An analysis of the UALCAN database and clinical specimens revealed an increase in ATOX1 expression in HCC tissues. In vitro studies showed that ATOX1 knockdown inhibited the proliferation and metastasis of HCC cells, as well as tumor growth in xenograft models. Silencing ATOX1 led to cuproptosis and mitochondrial dysfunction in HCC cells. In contrast, ATOX1 overexpression had opposite effects. The ATOX1 promoter region was predicted to contain several paired related homeobox 2 (PRRX2) binding sites based on the JASPAR database. Further experiments showed that PRRX2 directly bound to ATOX1's promoter and positively regulated its expression. The knockdown of PRRX2 led to the inhibition of cell proliferation, invasion, and EMT, while promoting cuproptosis in HCC cells. However, these effects were found to be partially blocked following the overexpression of ATOX1. The study showed that ATOX1, which is transcriptionally activated by PRRX2, contributes to HCC carcinogenesis by regulating cancer cell malignant behaviors, cuproptosis, and mitochondrial function. The PRRX2/ATOX1 axis could be a potential therapeutic target for HCC.