DGAT1 Drives Racially Divergent Fibroblast Activation via ERK1/2-Dependent Tumorigenic Signaling in Prostate Cancer

Lethal prostate cancer (PCa) disproportionately affects African American (AA) men, who experience a higher incidence and earlier onset compared to European American (EA) men, reflecting a persistent biological and clinical disparity. Recent studies have implicated race-associated differences in lipid metabolic reprogramming as key contributors to this disparity. We recently identified carcinoma-associated fibroblasts (CAFs) as a major stromal component that mediates racial disparities in tumor progression. Here, we demonstrate that lipid-laden CAF from AA patients (AACAF) display enhanced pro-tumorigenic properties compared with CAFs from EA patients (EACAF). Lipid droplet (LD) biogenesis and storage analysis revealed a robust diacylglycerol O-acyltransferase 1 (DGAT1) enzyme-dependent LD accumulation in AACAF. Ectopic DGAT1 expression in benign fibroblasts induced CAF markers (FAP1 and ⍺SMA) expression linked to fibroblast activation, altered the secretome, and significantly enhanced PCa cells' growth in vivo. Integrative transcriptomic and secretome analyses identified novel DGAT1-regulated genes involved in CAF linked to metabolism, cell-cell communication, motility, and angiogenesis, mediated mainly through ERK1/2 signaling activation. Pharmacological DGAT1 inhibition suppressed these pathways and elicited racially distinct regulation of tumor-promoting mediators, including BDNF, VEGF, and TSP1. Mechanistic experiments show that functionally, lipid-laden CAF from AA patients exhibit increased fibroblast activation and a secretory phenotype with greater pro-tumor activity compared to CAF from EA patients. Collectively, these findings reveal that DGAT1 is a pivotal enzymatic regulator of fibroblast activation and lipid-driven remodeling in the PCa tumor microenvironment (TME) of AA men. Targeting DGAT1 represents a promising strategy to disrupt metabolic-stromal crosstalk and mitigate race-associated disparities in PCa progression.