Minimal-length CAG repeats in AR define a hyperactive AR–LSD1 axis driving metabolic reprogramming in prostate cancer

The polymorphic CAG trinucleotide repeat in the androgen receptor (AR) gene encodes a variable-length N-terminal polyglutamine (polyQ) tract that modulates AR transcriptional activity, with shorter tracts generally enhancing AR activity. While the majority of men harbor CAG repeats longer than 17, a small subset carry minimal-length CAG repeats (≤17) in AR. These alleles are primarily found in men of African ancestry, accounting for over 10% of the population, and may significantly contribute to the increased prostate cancer (PCa) risk and worse clinical outcomes observed in this population. However, how this distinct pattern of polymorphism influences AR–chromatin interaction, metabolic reprogramming, and therapeutic response remains unclear. Here, we established isogenic PCa cell lines harboring AR with a minimal length of CAG repeats that encode an ultrashort polyQ tract and found that this AR variant exhibits attenuated response to AR-targeted therapies with markedly enhanced protein stability, expanded chromatin binding, and a reprogrammed transcriptional profile. The ultrashort polyQ AR also reshapes global FOXA1 occupancy and upregulates metabolic gene networks, leading to enhanced glycolysis and reduced mitochondria respiration. Mechanistically, we identify a strengthened AR–LSD1 interaction and show that LSD1 inhibition suppresses the expanded AR chromatin binding, impairs the glycolytic reprogramming, and reduces tumor growth. Together, these findings define a hyperactive AR–LSD1 chromatin axis driven by minimal-length CAG repeats in AR and reveal a mechanistic link between inherited AR polymorphism, AR-mediated epigenetic-metabolic remodeling, and population-associated disparities in prostate cancer biology.