The FGFRL1-FASN axis regulates neuroendocrine lineage transdifferentiation by modulating fatty acid synthesis in AR pathway-independent prostate cancer.

AR pathway-independent prostate cancer (ARIPC), particularly neuroendocrine prostate cancer (NEPC), represents one of the most lethal states of metastatic castration-resistant prostate cancer. However, how fatty acid synthesis (FAS) is organized in ARIPC and whether distinct lipogenic states shape neuroendocrine lineage transdifferentiation remain unclear. By integrating single-cell and bulk transcriptomic analyses of mCRPC cohorts, we identify NEPC as a fatty-acid-synthesis-low state associated with poor survival. Within this context, fatty acid synthase (FASN) emerges as a key indicator and functional contributor to lipogenic activity. FASN depletion suppresses lipogenesis while increasing NEPC-associated programs, migration, and metastatic colonization. We further identify FGFRL1 as the FGF family member most consistently associated with fatty acid synthesis activity in ARIPC. FGFRL1 depletion reduces FASN expression and relative free fatty-acid content, while targeted GC-MS supports broader fatty-acid remodeling and fluorescent uptake assays show increased exogenous fatty-acid uptake. FASN restoration partially restores relative free fatty-acid content and attenuates NEPC-associated and migratory phenotypes. Directional perturbation, rescue, AKT phosphorylation, and co-immunoprecipitation analyses further support the functional FGFRL1-FASN relationship. ONECUT2 is prioritized as a candidate downstream transcriptional regulator whose expression correlates with the neuroendocrine program. Together, these findings support an FGFRL1-FASN metabolic axis that regulates neuroendocrine lineage transdifferentiation and metastatic progression in ARIPC.