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Although metabolic and signaling molecules are increasingly recognized as modulators of tumor progression, their role in cell fate transition remains unclear. NE (neuroendocrine) tumors produce and accumulate serotonin, a neurotransmitter that regulates diverse physiologic processes. In this study, we identify a tumor-intrinsic serotonin axis as a key driver of NEPC lineage commitment and progression. NEPC endogenously synthesizes serotonin via aromatic L-amino acid decarboxylase (AADC; encoded by DDC) and reuptakes it through the transporter SLC6A4. Mechanistically, high levels of intracellular serotonin promote histone serotonylation at H3K4me3Q5, reconfiguring the H3K4me3 chromatin landscape and downstream gene expression, which drives NE differentiation and is associated with suppressed androgen receptor signaling. Pharmacologic inhibition of serotonin synthesis using the FDA-approved DDC inhibitor carbidopa significantly impairs tumor growth and prolongs survival in both genetically engineered and patient-derived xenograft models, highlighting histone serotonylation as a druggable vulnerability in NEPC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Collectively, our findings uncover an epigenetically embedded, serotonin-driven lineage program in NEPC, coupling tumor-intrinsic serotonin metabolism with tumor cell fate control, and identify histone serotonylation as a tractable therapeutic vulnerability in lineage-plastic prostate cancer.<\/jats:p>\n                  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