Tip60‐Mediated USP22 Lactylation Drives Glutamine Metabolic Reprogramming via SLC25A5 in TNBC

Glutamine metabolism promotes breast cancer progression and metastasis, though the underlying mechanisms are not fully understood. In this study, we identified a significant positive correlation between glutamine metabolism and ubiquitin-specific protease 22 (USP22)expression in breast cancer patients. USP22 drives glutamine reprogramming to promote lactate secretion, thereby supporting triple-negative breast cancer (TNBC) growth and survival. This process involves the lactyltransferase Tat-interactive protein, 60 kDa (Tip60), which catalyzes K134 lactylation of USP22. This post-translational modification (PTM) stabilizes USP22 protein levels and facilitates its mitochondrial location. Moreover, USP22 stabilizes the solute carrier family 25 member 5 (SLC25A5) through its de-ubiquitinase activity. Clinically, increased expression levels of both USP22 and SLC25A5 are significantly associated with a poor prognosis in patients with TNBC. Furthermore, USP22 regulates glutamine metabolism to promote α-ketoglutarate (α-KG) secretion, thereby activating M2 macrophages and suppressing the anti-tumor immune response. Importantly, targeting USP22 synergized with CB-839 in TNBC xenograft models. These findings underscore USP22 as a promising therapeutic target for TNBC.