Tumor-derived lactate fuels the STAT3-LCN2 pathway to promote bladder cancer malignancy and chemoresistance.

Bladder cancer progression is closely linked to metabolic changes within the tumor microenvironment (TME), particularly elevated lactate levels. Lipocalin 2 (LCN2), a protein involved in iron regulation, has been implicated in tumor progression in several cancers, but its regulatory mechanisms and role in bladder cancer remain unclear. Bladder cancer cell lines were treated with exogenous lactate or subjected to inhibition of endogenous lactate production to evaluate changes in LCN2 expression. The role of Signal Transducer and Activator of Transcription 3 (STAT3) was assessed using genetic knockdown and pharmacological inhibitors. Functional assays including migration, epithelial-to-mesenchymal transition (EMT), sphere formation, and stemness marker analysis were performed to determine the biological effects of LCN2. Chemoresistance to gemcitabine was examined with and without LCN2 silencing. Clinically, LCN2 expression was significantly associated with the pathological relevance of bladder tumors. Lactate significantly induced LCN2 expression in bladder cancer cells through activation of STAT3. Disruption of STAT3 signaling reduced LCN2 levels. High LCN2 expression correlated with advanced tumor grade, poor prognosis, and shorter overall survival. Functionally, LCN2 promoted EMT, enhanced cell migration, and increased stem cell-like properties, as evidenced by elevated stemness markers and sphere-forming ability. Moreover, lactate-induced LCN2 expression conferred resistance to gemcitabine treatment, while LCN2 knockdown restored chemosensitivity. This study identifies tumor-derived lactate as a key inducer of LCN2 expression via STAT3 activation in bladder cancer. LCN2 contributes to tumor aggressiveness, cancer stemness, and chemoresistance. Targeting the STAT3-LCN2 signaling axis may offer a promising therapeutic strategy to suppress bladder cancer progression and overcome treatment resistance within a lactate-rich TME.