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Recent studies have revealed that this reprogramming is mediated by previously unrecognized coactivators, including CXXC5, TET2, and EZH2, which cooperate with AR to establish a transcriptional landscape that supports lineage plasticity and therapeutic evasion. These noncanonical AR transcriptional programs enable CRPC cells to survive under continued AR blockade, acting as a transitional state towards neuroendocrine differentiation. Pharmacologic disruption of these coactivators abrogates noncanonical AR activity and suppresses tumor growth, highlighting a tractable vulnerability. These findings redefine AR signaling in advanced disease, suggesting that targeting noncanonical AR coactivators could offer a novel therapeutic paradigm to overcome resistance. Advances in single-cell and epigenomic profiling are poised to delineate further the heterogeneity and dynamics of AR cistrome remodeling in treatment-refractory prostate cancer.<\/jats:p>","DOI":"10.3389\/fonc.2025.1748527","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T05:42:56Z","timestamp":1768196576000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Coactivator networks orchestrating noncanonical AR programs in enzalutamide-resistant CRPC"],"prefix":"10.3389","volume":"15","author":[{"given":"Ephraim 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