METTL5-mediated rRNA modification controls prostate cancer progression through the IRF7/DNA2 axis and mitophagy regulation.

Prostate cancer progression to advanced disease is accompanied by extensive metabolic rewiring, yet the upstream regulatory mechanisms remain incompletely defined. Here, we showed that the rRNA m6A methyltransferase METTL5 was progressively upregulated during prostate cancer progression and was associated with poor patient survival. Mechanistically, METTL5 catalyzed N6-methyladenosine (m6A) modification at A1832 of 18S rRNA, thereby enhancing overall translational output and promoting prostate cancer cell proliferation in vitro and tumor growth in vivo. Integrative transcriptomic and proteomic analyses further revealed that METTL5-dependent rRNA modification preferentially increased translation of mRNAs harboring a GCACGN(2-4)CC motif within their 5' untranslated regions. Among these targets, the transcription factor IRF7 was selectively upregulated and directly induced DNA2 transcription. DNA2, a mitochondrial nuclease required for mitochondrial DNA maintenance, preserves oxidative phosphorylation capacity in prostate cancer cells. Disruption of the METTL5/IRF7/DNA2 axis led to mitochondrial dysfunction, increased reactive oxygen species, and compensatory mitophagy, ultimately suppressing tumor growth. Notably, neither IRF7 nor METTL5 overexpression rescued the growth defects caused by DNA2 depletion, supporting a hierarchical organization of this pathway with DNA2 as an essential downstream effector. Finally, therapeutic inhibition of METTL5 using locked nucleic acids markedly suppressed prostate cancer growth in vivo without evident systemic toxicity, underscoring translational potential. Collectively, our findings uncover an unappreciated mechanism linking rRNA modification to mitochondrial homeostasis through selective translational control, providing new insights into metabolic regulation and revealing actionable vulnerabilities in advanced prostate cancer.