Functional and Mechanistic Insights of 3-Hydroxybutyrate (3-OBA) in Bladder Cancer.

Bladder cancer (BC), particularly muscle-invasive urothelial bladder carcinoma (UBC), remains a clinical challenge due to frequent recurrence, chemoresistance, and limited treatment options. This study investigates the functional and mechanistic insights of 3-hydroxybutyrate (3-OBA), a ketone body with known metabolic and epigenetic roles, in muscle-invasive UBC models. 3-OBA significantly inhibited cell viability, proliferation, migration, and invasion in T24 and HT1376 cell lines in a dose-dependent manner. In vivo, 3-OBA impaired tumor growth and angiogenesis in the chick chorioallantoic membrane model. Mechanistically, 3-OBA did not alter the expression of the G-protein-coupled lactate receptor GPR81 or associated markers (phospho-ERK1/2, LDHA, MCT1/4, CD147), indicating its antitumor effects are GPR81-independent. Moreover, extracellular lactate modulation upon 3-OBA treatment varied between cell lines, with HT1376 cells showing reduced lactate production under nutrient deprivation, suggesting cell-specific metabolic responses to 3-OBA. These findings highlight 3-OBA's potential as a metabolic modulator with antitumor efficacy in UBC, particularly in metabolically constrained tumors. However, its dual role-as both a potential energy source and therapeutic agent-demands context-specific investigation. Future studies should focus on patient stratification and preclinical validation to clarify 3-OBA's therapeutic window and mechanism of action in bladder cancer.