METTL5 promotes fatty acid metabolism by modulating peroxisome to induce hepatocellular carcinoma recurrence after thermal ablation

Thermal ablation (TA) (e.g., radiofrequency ablation [RFA]) is a critical curative therapy for hepatocellular carcinoma (HCC). However, the high recurrence rate of HCC after ablation remains a major clinical challenge. Hyperactive mRNA translation mediated by aberrant RNA modifications is vital for tumor heat stress adaptation. One of the most prevalent rRNA modifications is 18S rRNA N⁶-methyladenosine (m⁶A) modification catalyzed by methyltransferase 5 (METTL5); however, the role of METTL5-mediated rRNA modification in HCC recurrence after RFA remains unknown. Here, we found that the levels of METTL5 and 18S rRNA m⁶A modification were significantly upregulated in post-RFA recurrent HCC and were further verified by insufficient RFA (iRFA) models in vitro and in vivo. Four mouse models, together with functional cell experiments, showed that METTL5 promoted HCC progression under heat stress. Mechanically, we demonstrated that heat-mediated METTL5 upregulation enhanced the PEX16 translation that promoted peroxisomal biogenesis and β-oxidation of very long-chain fatty acid, which promoted mitochondrial respiration to mediate HCC progression. Our study reveals the novel mechanistic insights in HCC recurrence after iRFA, demonstrating the important role of heat stress-mediated tumor metabolism adaptation by mRNA translation in HCC development. These findings identify METTL5 as a potential therapeutic target to prevent and treat HCC recurrence after TA.