FABP4 characterizes metabolic-immune interactions and serves as a prognostic biomarker across gynecologic...

Gynecological malignancies-including breast, cervical, ovarian, endometrial cancers and uterine sarcoma-pose a serious threat to women's health owing to their high incidence, aggressiveness and frequent recurrence. Fatty acid-binding protein 4 (FABP4) is a key regulator of lipid metabolism and tumor metabolic reprogramming, yet systematic investigations of its role across gynecological malignancies remain scarce. Here, by integrating data from TCGA, GTEx and multiple public repositories, we performed a multi-omics, multi-scale analysis of five gynecological malignancies, encompassing transcriptomics, DNA methylation, copy-number variation (CNV), single-cell RNA sequencing and spatial transcriptomics. FABP4 was markedly downregulated in most gynecological tumors, and its expression correlated significantly with tumor grade, clinical stage and patient prognosis, demonstrating robust diagnostic performance. Survival analyses revealed a tumor-type-dependent prognostic value: high FABP4 expression was associated with poor outcomes in ovarian and cervical cancers, but with favorable prognosis in endometrial cancer. Methylation, CNV and somatic mutation analyses indicated that FABP4 downregulation is significantly associated with promoter hypermethylation, suggesting that epigenetic silencing is a major contributing mechanism. Single-cell and spatial transcriptomic profiling localized FABP4 expression mainly to stromal populations-particularly endothelial cells and fibroblasts-and revealed close associations with the tumor immune microenvironment. Drug sensitivity analyses further identified several small-molecule compounds capable of reversing FABP4 dysregulation-associated transcriptional signatures, targeting key oncogenic pathways including PI3K/mTOR, RTK signaling and the cell cycle. Collectively, this study delineates the expression patterns, molecular mechanisms and microenvironmental functions of FABP4 across gynecological malignancies, providing a foundation for its application as a diagnostic and prognostic biomarker and as a potential therapeutic target.