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The role of transcription factors (TFs) in PCa progression and NEPC transdifferentiation remains inadequately understood, underscoring a critical gap in current research. In this study, an internal Z score\u2010based approach is developed to identify lineage\u2010specific TF profiles in prostatic adenocarcinoma and NEPC for a nuanced understanding of TF expression dynamics. Distinct TF profiles for adenocarcinoma and NEPC are unveiled, identifying 126 shared TFs, 46 adenocarcinoma\u2010TFs, and 56 NEPC\u2010TFs, validated across multiple cohorts. Gene Ontology is employed to validate their biological and functional roles in PCa progression. Implications are revealed in cell development, differentiation, and lineage determination. Knockdown experiments suggest that lineage\u2010TFs are functionally important in maintaining lineage\u2010specific cell proliferation. 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