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Triple-negative breast cancer (TNBC) is a malignancy with high metastasis rate and poor prognosis. Limited drugs are effective for the treatment of TNBC patients. Ubiquitin specific proteases (USPs) are important posttranscription modulators that promote protein stability by reducing the ubiquitination of the proteins. Aberrant expression of USPs is involved in the development of numerous cancers. However, it remains poorly understood on the role of USP46 in TNBC growth and metastasis. In this study, we explored the clinical relevance, function and molecular mechanisms of USP46 in TNBC. USP46 expression was increased in breast cancer tissues. High expression of USP46 was associated with the poorer prognosis of the patients. Overexpression and knockdown experiments demonstrated that USP46 was critical for TNBC cell growth, migration, and tumorigenesis. Mechanistically, USP46 enhanced the protein stability of phosphoglycerate mutase 1 (PGAM1) via direct interaction. Importantly, USP46 stimulated the glycolysis and promoted the malignant growth of TNBC cells through upregulation of PGAM1. Our study reveals that USP46/PGAM1 axis contributes to TNBC progression and is a potential target for the treatment of TNBC patients.