GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE313nnn/GSE313088/primaryOK200TranscriptomicsHomo sapiensExpression profiling by arrayhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE313088GEOGSEfalseTranscriptomic Profiling Identifies the Cyclin D–CDK4/6 Axis as a Druggable Mediator of Cisplatin Resistance in Bladder Cancer [array]Purpose Cisplatin resistance remains a critical challenge in bladder cancer (BC). This study aimed to define molecular drivers of cisplatin resistance and to assess potential therapeutic targets that may help restore treatment responsiveness. Methods Integrative transcriptomic analyses were performed using The Cancer Genome Atlas (TCGA) cohort to compare cisplatin non-responders with responders, alongside a cisplatin-resistant BC cell model to identify dysregulated pathways. Functional studies, including siRNA-mediated knockdown, SRB viability assays, flow cytometry, western blotting, and microarray-based transcriptomics, were used to characterize the dysregulated pathways. Results Both TCGA data and resistant BC cells exhibited upregulation of CCND1 and enrichment of E2F target genes. Silencing of Cyclin D1 restored cisplatin sensitivity in resistant cells. Abemaciclib selectively inhibited proliferation of cisplatin-resistant BC cells, reduced RB phosphorylation, induced sub-G1 accumulation, and suppressed expression of key regulators of cell-cycle progression and homologous recombination repair. Combined treatment with abemaciclib and cisplatin synergistically suppressed the proliferation of cisplatin-resistant BC cells in vitro and resulted in significantly greater tumor growth inhibition in an RT112 xenograft model in vivo. Conclusion Activation of the Cyclin D1/CDK4/6–E2F axis is a key driver of cisplatin resistance and demonstrate that CDK4/6 inhibition reduces proliferative capacity and DNA repair competency while enhancing cisplatin responsiveness. Targeting this pathway represents a rational therapeutic strategy for advanced or refractory BC.2026/06/18GSE313088GSM9360742GSM9360743GSM9360740GSM936074121282313088Homo sapiens[42045965]