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

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.