N 6-methyladenosine–dependent ARv7 translation couples lactate metabolism with enzalutamide resistance in prostate cancer

Enzalutamide (Enz)–resistant prostate cancer (PCa) is a lethal disease that affects a broad population of elderly men. Experimental and clinical evidence has demonstrated that androgen receptor variant 7 (ARv7) plays a critical role in Enz-resistant (EnzR) PCa by functioning as a constitutively active transcription factor driving disease progression. However, the predictive value of the ARv7 transcript has not been fully recognized due to its low frequency in castration-resistant PCa. In this study, we identified ARv7 mRNA as an N 6-methyladenosine (m ⁶ A)–modified transcript. Enz treatment increases METTL3-dependent m ⁶ A methylation of ARv7 mRNA at the A1177 site, which is subsequently recognized by the reader protein YTHDC2, leading to enhanced translation efficiency of ARv7. Furthermore, EnzR PCa exhibited elevated lactate metabolism, which regulated AR transcription through promoter-mediated epigenetic modifications at H3K9 and H3K14. Reactivated AR exhibited enhanced phase separation to transcriptionally up-regulate YTHDC2 expression. In vivo experiments demonstrated that targeting the METTL3-YTHDC2-ARv7 axis represents a promising therapeutic strategy to suppress EnzR PCa progression. Moreover, the METTL3 inhibitor STM2457 synergized with Enz to inhibit tumor growth without observable toxicity. Collectively, our findings suggest that the clinical utility of ARv7 may need to be reconsidered in light of its m ⁶ A-dependent translational regulation.