Bladder cancer progression is intrinsically linked to epithelial-mesenchymal transition (EMT), a protein-centric process driving metastasis and therapy resistance. This study systematically dissected bladder cancer transcriptomes through the lens of VIM (vimentin) and CDH2 (N-cadherin) protein networks, integrating datasets from GEO via cross-platform harmonization. Non-negative matrix factorization (NMF) resolved two molecular subtypes with distinct EMT-related protein expression profiles, characterized by asymmetric transcriptomic dysregulation. Functional enrichment revealed protein-driven pathways-including TGF-β signaling, Wnt/β-catenin activation, and ECM remodeling-as hallmarks of aggressive subtypes. LASSO regression identified 384 transcriptional drivers, while PPI network analysis prioritized 10 hub proteins (CALML5, THBS1, SMAD7, TAGLN, ICAM1, CEBPB, CNN1, TNFAIP3, TNFRSF1A, EFEMP2) via maximum clique centrality (MCC). Critically, TAGLN, CNN1, THBS1, and SMAD7 exhibited significant co-expression with VIM and CDH2 (correlation coefficients >0.1), implicating their roles in cytoskeletal protein assembly (TAGLN, CNN1), matricellular signaling (THBS1), and TGF-β pathway regulation (SMAD7). Functional validation confirmed these hub proteins as central to EMT plasticity, with TAGLN-VIM/CDH2 co-activation (r = 0.55 and 0.24, respectively) driving actin polymerization and protein-mediated invasion. SMAD7 further modulated TNFRSF1A-TNFAIP3 crosstalk to sustain mesenchymal phenotypes. This multi-omics framework delineates VIM/CDH2-centric protein interactomes as therapeutic vulnerabilities, proposing TAGLN/THBS1-targeted strategies to disrupt EMT-driven metastasis. By anchoring molecular subtyping and drug discovery in protein network topology, this work advances precision oncology for bladder cancer, bridging transcriptomic heterogeneity to actionable protein targets.