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<p>Muscle-invasive bladder cancer (MIBC) remains highly aggressive. We identified the long non-coding RNA RMRP as significantly upregulated in MIBC. Functional studies demonstrated that RMRP promotes invasive phenotypes and glycolytic reprogramming. Mechanistically, RMRP binds pyruvate dehydrogenase complex X component (PDHX) and weakens the PDHX–dihydrolipoamide dehydrogenase (DLD) interaction, thereby impairing pyruvate dehydrogenase complex (PDC) function, reducing pyruvate dehydrogenase (PDH) activity, and shifting pyruvate metabolism toward lactate production. The resulting lactate promotes p300-dependent lactylation of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) at K272 and K561, thereby stabilizing IGF2BP1 by reducing ubiquitin-mediated degradation. Stabilized IGF2BP1, in turn, binds to RMRP and stabilizes it. This establishes an RMRP-PDHX-lactate-IGF2BP1 positive feedback loop that continuously amplifies the invasive phenotype of MIBC. These findings reveal a novel mechanism by which RMRP promotes invasion through metabolic reprogramming and lactylation-mediated feedback, highlighting a potential therapeutic target for MIBC.</p><p></p>

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LncRMRP drives bladder cancer invasion via a lactylation-driven positive feedback circuit

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • Yuting Gao,
  • Chen Chen,
  • Ruixin Sun,
  • Yiwen Yao,
  • Xueru Zhang,
  • Wenqiang Quan,
  • Jing Li,
  • Ping Ji,
  • Junlu Wu,
  • Huarong Luo,
  • Dong Li,
  • Zujun Sun

摘要

Muscle-invasive bladder cancer (MIBC) remains highly aggressive. We identified the long non-coding RNA RMRP as significantly upregulated in MIBC. Functional studies demonstrated that RMRP promotes invasive phenotypes and glycolytic reprogramming. Mechanistically, RMRP binds pyruvate dehydrogenase complex X component (PDHX) and weakens the PDHX–dihydrolipoamide dehydrogenase (DLD) interaction, thereby impairing pyruvate dehydrogenase complex (PDC) function, reducing pyruvate dehydrogenase (PDH) activity, and shifting pyruvate metabolism toward lactate production. The resulting lactate promotes p300-dependent lactylation of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) at K272 and K561, thereby stabilizing IGF2BP1 by reducing ubiquitin-mediated degradation. Stabilized IGF2BP1, in turn, binds to RMRP and stabilizes it. This establishes an RMRP-PDHX-lactate-IGF2BP1 positive feedback loop that continuously amplifies the invasive phenotype of MIBC. These findings reveal a novel mechanism by which RMRP promotes invasion through metabolic reprogramming and lactylation-mediated feedback, highlighting a potential therapeutic target for MIBC.