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

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 Cau 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 for disrupting metabolic-stromal crosstalk to mitigate race-associated disparities in PCa progression.