Mint3 suppresses cuproptosis by modulating the AHR signalling pathway to facilitate the progression of hepatocellular carcinoma.

We screened genes from multiple datasets that were highly expressed in hepatocellular carcinoma (HCC) and associated with prognosis, and identified Mint3 as an important oncogene. Mint3 is implicated in controlling the malignant behaviours of pancreatic and breast cancer cells; however, our understanding of its role in HCC remains limited. Bioinformatic analysis of the underlying mechanisms showed that Mint3 may accelerate HCC development by suppressing cuproptosis. Cuproptosis, a novel copper-induced mode of cell death, may be associated with tumour progression. However, its involvement in tumourigenesis, metastasis, and patient prognosis requires further investigation. In this study, we aimed to identify novel biomarkers for HCC that may improve the prognosis of patients with HCC. We also investigated whether Mint3 regulated cuproptosis in HCC cells. Our results showed that Mint3 expression was frequently elevated in HCC specimens and was associated with increased tumour size, advanced tumour-node-metastasis stage, higher pathological grade, and poorer survival. Mint3 affected cell morphology and promoted proliferation, migration, and the epithelial-mesenchymal transition of HCC cells. Furthermore, our findings revealed that Mint3 overexpression resulted in reduced cuproptosis in HCC cells. The overexpression/down-regulation of FDX1, which is a critical mediator of cuproptosis, reversed Mint3 overexpression/downregulation-induced alterations of malignant phenotypes of HCC cells. Mechanistically, Mint3 exerted this effect via direct interaction with AHR, thus modulating the AHR signalling pathway and promoting AHR nuclear translocation. Further research demonstrated that AHR binds to the promoter region of FDX1 and subsequently inhibits it. Meanwhile, Mint3 knockdown suppressed HCC progression in patient-derived xenograft models. In the Mint3-knockout mouse group, Tp53 knockout/c-Myc overexpression treatment induced less spontaneous tumour formation than that in the WT group. Collectively, Mint3 is overexpressed in HCC and contributes to HCC progression by inhibiting cuproptosis via the AHR signalling pathway. Therefore, Mint3 may serve as a potential biomarker and therapeutic target in HCC.