LHX2 Rewires the Metabolic and Epigenetic Landscape to Drive Tumor Progression in Prostate Cancer

Abstract Neuroendocrine prostate cancer (NEPC) evolves as an aggressive phenotype during prolonged androgen deprivation therapy, lacking effective clinical management. In this study, we elucidated a reciprocal metabolic–epigenetic mechanism involving a positive feedback loop between glycolysis and the transcription factor LHX2 that promotes prostate cancer progression. Mechanistically, enzalutamide-mediated inhibition of the androgen receptor led to upregulation of key glycolytic enzymes. Elevated glycolysis resulted in lactate accumulation and subsequent histone lactylation, which in turn enhanced LHX2 expression. Reciprocally, LHX2 transcriptionally activated the lactate dehydrogenase LDHA, which further amplified lactate production. Furthermore, LHX2 augmented the expression of the lineage-determining enzyme DNMT1, potentiating neuroendocrine gene expression and tumor growth. Significantly, the antiviral agent paritaprevir could directly bind to LHX2, effectively suppressing neuroendocrine marker expression and tumor progression. These findings uncover a potential role for LHX2 in orchestrating NEPC development, offering putative therapeutic targets for treating this aggressive cancer phenotype and overcoming drug resistance. Significance: LHX2 bridges metabolic reprogramming and epigenetic rewiring to drive tumor progression via DNMT1, providing a mechanism of neuroendocrine transdifferentiation and the rationale for developing a potential therapeutic strategy for neuroendocrine prostate cancer.