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Our previous work identified CDK12 as a critical regulator of prostate cancer (PCa) cell survival under sustained enzalutamide exposure, though the precise mechanism remains to be elucidated. In this study, we hypothesize that CDK12 plays a key role in mitophagy regulation under mitochondrial stress, potentially modulating PCa cell resistance to enzalutamide, the first\u2010line clinical medication in PCa therapy. Utilising multiple in\u00a0vitro PCa cell models, we demonstrate that both CDK12 knockdown and pharmacological inhibition with THZ531 impaired mitophagy following treatment with enzalutamide and mitophagy inducer CCCP. Mechanistically, our finding reveal that CDK12 inhibition disrupts FOXO3\u2010induced BNIP3 transcription, thereby preventing receptor\u2010mediated mitophagy and sensitising PCa cells to enzalutamide. This study identifies the CDK12\u2010FOXO3\u2010BNIP3 pathway as a novel regulatory mechanism governing mitophagy under mitochondrial stress. Importantly, these results underscore CDK12's role in preserving mitochondrial function and promoting PCa cell survival during enzalutamide treatment. These findings highlight the therapeutic potential of targeting the CDK12\u2010BNIP3\u2010mitophagy axis in combination with antiandrogen therapies, offering a promising strategy to overcome drug resistance in PCa and improve clinical outcomes.<\/jats:p>","DOI":"10.1111\/cpr.70091","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:30:51Z","timestamp":1751502651000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>CDK12<\/scp>\n                    Inactivation Attenuates Prostate Cancer Progression by Inhibiting\n                    <scp>BNIP3<\/scp>\n                    \u2010Mediated Mitophagy"],"prefix":"10.1111","volume":"59","author":[{"given":"Mengjun","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Urology, Pelvic Floor Disorders Center The Seventh Affiliated Hospital, Sun Yat\u2010sen University  Shenzhen 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