A positive SPTBN2-FLI1 feedback axis promotes bladder cancer via PI3K/AKT activation.

Bladder cancer (BLCA) is characterized by high recurrence rates and limited treatment efficacy in advanced stages, prompting investigation into the role of SPTBN2 in BLCA pathogenesis and its potential as a prognostic biomarker and therapeutic target. Analysis of BLCA patient samples revealed significant SPTBN2 overexpression, which independently correlated with poor clinical outcomes. Functional assays demonstrated that SPTBN2 knockdown suppressed malignant phenotypes, including proliferation, migration, and colony formation in BLCA cell lines. Mechanistically, a reciprocal regulatory loop between SPTBN2 and the transcription factor FLI1 was identified, driving tumor progression through activation of the PI3K/AKT pathway and induction of epithelial-mesenchymal transition. Pharmacological inhibition of PI3K effectively counteracted the oncogenic effects mediated by SPTBN2 in both in vitro and in vivo models. These findings establish SPTBN2 as a novel oncoprotein and prognostic biomarker in BLCA, and highlight the SPTBN2-FLI1-PI3K/AKT axis as a promising therapeutic target for intervention.