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Background: The implication of zinc finger protein 148 (ZNF-148) in pathophysiology of most human cancers has been reported; however, the biological functions of ZNF-148 in breast cancer remain unclear. This study sought to elucidate the potential molecular mechanism of ZNF-148 on breast cancer pathology., Methods: ZNF148 expression was tested in breast cancer tissues and cells. Then, cells were transfected with ZNF-148 overexpression or downregulation vector, and the cell proliferation, pyroptosis, apoptosis, and reactive oxygen species (ROS) production were analyzed by MTT, western blot, flow cytometry, and immunofluorescence staining, respectively. Tumor-bearing nude mouse was used to evaluate tumorigenesis of ZNF-148. Mechanisms underpinning ZNF-148 were examined using bioinformatics and luciferase assays., Results: We found that ZNF-148 was upregulated in breast cancer tissues and cell lines. Knockdown of ZNF-148 suppressed malignant phenotypes, including cell proliferation, epithelial-mesenchymal transition, and tumorigenesis in vitro and in vivo, while ZNF-148 overexpression had the opposite effects. Further experiments showed that ZNF-148 deficiency promoted ROS production and triggered both apoptotic and pyroptotic cell death, which were restored by cotreating cells with ROS scavengers. A luciferase reporter assay revealed that miR-335 was the downstream target of ZNF-148 and that overexpressed ZNF-148 increased superoxide dismutase 2 (SOD2) expression by sponging miR-335. In parallel, both miR-335 downregulation and SOD2 overexpression abrogated the antitumor effects of ZNF-148 deficiency on proliferation and pyroptosis in breast cancer cells., Conclusions: Our findings indicated that ZNF-148 promotes breast cancer progression by triggering miR-335/SOD2/ROS-mediated pyroptotic cell death and aid the identification of potential therapeutic targets for breast cancer., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)