The deubiquitinating enzyme regulatory network in malignant progression of breast cancer encompasses mechanisms of action, clinical significance and emerging therapeutic targets

Abstract Purpose Breast cancer progression is orchestrated by a networked regulatory architecture of deubiquitinases (DUBs), defined by functional convergence, pathway pleiotropy, and complementary parallel layers. This review elucidates how this integrated circuitry governs breast cancer malignancy, therapy resistance, and immune evasion, and evaluates its clinical translational potential. Methods We comprehensively reviewed recent literature on DUBs in breast cancer, synthesizing findings on molecular mechanisms, substrate specificity, pathway crosstalk, and clinical correlations across breast cancer subtypes. Results DUBs stabilize transcription factors (FOXM1, SNAI2), epigenetic modifiers (LSD1), and signaling nodes (ERα, HER2, MYC) to drive proliferation and stemness maintenance. In ERα-positive disease, convergent DUBs including USP36, USP22, USP15, and USP1 amplify ligand-dependent signaling and enable acquired endocrine resistance through stabilization of both wild-type and mutant ERα. DUBs accelerate cell cycle via USP14-CDK1 and promote metastasis through parallel USP20-SNAI2, USP28-Snail1, and USP41-Snail axes. Metabolically, OTUB1-MYC drives aerobic glycolysis, while USP11-PGAM5, USP24-DHODH, and USP5-GPX4 constitute complementary non-redundant ferroptosis defense layers particularly active in triple-negative breast cancer. DUBs also mediate DNA repair fidelity (USP4-BRCA1) and multidrug resistance (USP7-ABCB1). Beyond cell-intrinsic functions, DUBs modulate the tumor immune microenvironment, with the DUBRI signature stratifying immunotherapy response and the FASN-USP5-GPX4 axis linking ferroptosis sensitization to immune re-activation. Clinically, aberrant DUB expression correlates with aggressive features and poor prognosis; DUB-based signatures and serum exosomal UCHL1 show promise as candidate biomarkers, though prospective validation is lacking. Pharmacological targeting of DUBs—using inhibitors against USP7, USP24, UCHL1, or FASN—demonstrates preclinical efficacy in experimental models, but none has yet entered clinical trials for breast cancer. Conclusion DUBs function as central signaling hubs orchestrating malignant progression, treatment resistance, and immune evasion in breast cancer, positioning them as promising prognostic biomarkers and therapeutic targets. Addressing challenges in isoform selectivity, context-dependent functions, and substrate specificity will be essential to realize their clinical potential.