Introduction Fatty acid metabolism (FAM) is essential for cancer cell proliferation and progression, contributing to membrane synthesis, energy storage, and signaling molecule production. However, effective therapeutic strategies targeting FAM are yet to be established in clinical practice. This study aimed to develop a novel FAM-related prognostic signature for bladder cancer (BLCA) and investigate its biological and clinical significance. Methods We analyzed 359 BLCA samples and constructed a four-gene FAM-RiskScore (FAMR) signature based on FAM-related genes. Unsupervised clustering was performed to classify BLCA into molecular subtypes. The FAMR model was validated using internal and external cohorts. Functional enrichment, immune infiltration, and single-cell RNA sequencing analyses were conducted to explore underlying biological mechanisms. In vitro experiments, including proliferation and migration assays, were performed in T24 and 5637 bladder cancer cells following MAOA knockdown. Results BLCA samples were classified into two subtypes (C1 and C2), with C1 showing better overall survival, enhanced steroid metabolism, downregulated chemokine signaling, and lower immune scores. The FAMR signature comprising PATZ1, TTC6, AEBP1, and MAOA was established. High FAMR scores–associated with low PATZ1, TTC6, MAOA, and high AEBP1 expression–predicted poor prognosis. FAMR positively correlated with pathways related to chemotaxis, inflammation, and cytoskeleton regulation, but negatively with fatty acid metabolism pathways. Higher FAMR scores were observed in females, patients aged 60, and advanced-stage tumors. Single-cell analysis revealed AEBP1 was mainly expressed in cancer-associated fibroblasts, while MAOA was enriched in cancer cells. Functional studies demonstrated that MAOA knockdown significantly enhanced proliferation and migration of bladder cancer cells in vitro. Discussion We developed and validated a novel FAM-related risk signature that effectively predicts prognosis in BLCA. Our findings highlight MAOA as a potential tumor suppressor in bladder cancer, warranting further investigation as a therapeutic target. This FAMR model may facilitate risk stratification and inform personalized treatment strategies for bladder cancer patients.
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