N6-methyladenosine-dependent ARv7 translation couples lactate metabolism with enzalutamide resistance in prostate cancer.

Enzalutamide treatment increases METTL3-dependent m6A methylation of ARv7 mRNA at A1177, and YTHDC2 recognition boosts ARv7 translation efficiency in enzalutamide-resistant prostate cancer.

• Why it matters: ARv7 is linked to enzalutamide-resistant prostate cancer progression, but its predictive value is limited by low transcript frequency in castration-resistant disease.
• What they did: The study mapped ARv7 as an m6A-modified transcript and showed Enz elevates METTL3-dependent m6A at A1177, which YTHDC2 reads to enhance ARv7 translation; it also connected EnzR lactate metabolism to AR transcription via H3K9/H3K14 epigenetic changes and phase separation-driven YTHDC2 upregulation.
• The result: In vivo, inhibiting the METTL3–YTHDC2–ARv7 axis suppressed EnzR progression, and combining the METTL3 inhibitor STM2457 with Enz inhibited tumor growth without observable toxicity, suggesting ARv7 clinical utility may need reconsideration.

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