FMOD marks a low-malignancy epithelial state in prostate cancer: an ECM-related prognostic signature with single-cell and functional validation.

Extracellular matrix (ECM) remodeling promotes prostate cancer progression, while the prognostic value and cellular context of ECM-related genes (ERGs) remain unclear. A 4-gene ERG signature for disease-free interval prediction was built using TCGA-PRAD data, and the hub gene Fibromodulin (FMOD) was validated in an external cohort via scRNA-seq, bulk deconvolution and siRNA knockdown. The signature stratified patient prognosis, and FMOD exerted the strongest protective effect. Despite higher bulk expression in tumor tissues, FMOD predicted better clinical outcomes. FMOD was enriched in a low-chromosomal-instability, low-proliferation epithelial subpopulation with enhanced stromal-immune crosstalk, and FMOD knockdown boosted cancer cell proliferation and colony formation. FMOD identifies a low-malignancy epithelial state linked to favorable prostate cancer prognosis, supporting cell state-resolved validation of ECM-related prognostic biomarkers.