MUC13 promotes cisplatin resistance in intrahepatic cholangiocarcinoma through regulation by histone H3K18 lactylation

Abstract Cisplatin resistance remains a major clinical challenge in intrahepatic cholangiocarcinoma (iCCA); however, its underlying mechanisms are poorly understood. Building on our previous study that identified Mucin 13 (MUC13) as an oncogenic driver, we aimed to investigate its contribution to cisplatin resistance. We uncovered a previously unrecognized positive feedback loop between MUC13 and histone H3K18 lactylation (H3K18la), which sustains metabolic reprogramming and drives cisplatin resistance. Mechanistically, MUC13 activates the β-catenin/c-Myc axis to upregulate the expression of glucose transporter GLUT1 and key glycolytic enzymes (HK2, PKM2, and LDHA), thereby enhancing lactate production. The resulting lactate level elevation increases H3K18la enrichment at the MUC13 promoter, transcriptionally upregulating MUC13 and reinforcing glycolytic reprogramming and resistance. Any disruption of this loop by LDHA inhibition, which reduces lactate-mediated H3K18 lactylation, alleviates cisplatin tolerance in vitro and in vivo models. Notably, patient-derived organoids with high MUC13 and H3K18la expression were effectively sensitized to cisplatin by the LDHA inhibitor GSK2837808A, highlighting the translational potential of targeting this feedback loop. Collectively, our findings identify a metabolic–epigenetic positive feedback circuit between H3K18la and MUC13 that contributes to cisplatin resistance in iCCA and highlights histone lactylation as a potentially targetable therapeutic vulnerability.