FASN Promotes Malignant Progression of Bladder Cancer by Regulating Lipid Metabolism via the ERK/PPAR Pathway.

Among urological cancers, bladder cancer (BC) is one of the main causes of morbidity and death. Although the lipogenic enzyme fatty acid synthase (FASN) is known to aid in the growth of tumors, its precise role and mechanism in bladder cancer remain unclear. The effects and mechanisms of FASN in BC are examined in this study. Using information from The Cancer Genome Atlas (TCGA), the expression and prognostic significance of FASN were examined. Functional assays, including CCK-8, apoptosis, Transwell, and scratch-wound experiments, were conducted in BIU-87 and T24 cells after FASN knockdown and treatment with the ERK activator TBHQ. Western blot analysis assessed key proteins of the ERK/PPARγ pathway, such as PPARα, PPARγ, and p-ERK1/2, along with the lipid metabolism marker CD36. Metabolite levels, including free fatty acids, acyl-coenzyme A, and triglycerides, were quantified. Finally, an in vivo subcutaneous xenograft model was established to validate these findings. In BC tissues, FASN expression was markedly increased and associated with lower overall survival. FASN knockdown increased apoptosis while inhibiting BC cell motility, invasion, and proliferation. These phenotypic changes were associated with downregulation of the ERK/PPARγ pathway and reduced fatty acid uptake and metabolite levels. Both in vitro and in vivo, treatment with TBHQ effectively reversed the tumor-suppressive effects and metabolic alterations induced by FASN knockdown, confirming the involvement of ERK signaling. This study therefore demonstrates that FASN promotes BC progression by modulating the ERK/PPARγ pathway and lipid metabolism. Targeting FASN or its upstream activator ERK could thus provide a therapeutic strategy to inhibit BC growth.