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The majority of CRPCs overexpress the epigenetic enzyme EZH2 and harbor alterations in the PI3K pathway, providing 2 targetable pathways outside of the androgen receptor. Here, we show that EZH2 inhibitors synergize with PI3K, AKT, or mTORC1 inhibitors to kill CRPC in vitro and promote tumor regression in vivo. Strikingly, these agents trigger a catastrophic energy crisis by cooperatively suppressing glycolysis, the TCA cycle, and oxidative phosphorylation before cell death. EZH2 and PI3K pathway inhibitors achieve this by respectively inhibiting 2 key regulators of metabolism, MYC and HIF-1A, while derepressing a proapoptotic stress sensor. Together, these studies reveal a promising therapeutic strategy for CRPC and demonstrate how metabolic plasticity can be fatally impaired by cotargeting upstream oncogenic nodes that converge on this important process.<\/jats:p>\n                  <jats:p\/>\n                  <jats:p>This study describes a promising therapeutic strategy for advanced prostate cancer that triggers metabolic collapse of tumors by combining agents suppressing epigenetic and oncogenic enzymes<\/jats:p>","DOI":"10.1172\/jci203835","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T16:01:06Z","timestamp":1781020866000},"source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic and oncogenic inhibitors converge to drive a metabolic catastrophe in castration-resistant prostate cancer"],"prefix":"10.1172","volume":"136","author":[{"given":"Rhea","family":"Sahu","sequence":"first","affiliation":[{"name":"Genetics Division, Department of Medicine, Brigham and 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