Targeting MUC16 suppresses malignant progression and chemoresistance in large-duct type intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA), a highly lethal subtype of liver cancer with increasing incidence and poor prognosis, displays profound molecular heterogeneity that limits therapeutic efficacy. Combining multi-omics with pathological subtyping in iCCA, we identified a strong association between the most aggressive molecular subtype and the large-duct pathological type, characterized by aberrant mucin overexpression and prominent myeloid cell infiltration. Through integrative analysis, MUC16 was identified as a key molecular marker specifically enriched in large-duct type intrahepatic cholangiocarcinoma (L-iCCA). Functional modulation of MUC16 markedly inhibited L-iCCA cell proliferation and migration. Furthermore, high-throughput drug screening identified the small-molecule compound OSMI-1 as a potent suppressor of MUC16 expression. Using primary iCCA cell lines and patient-derived organoids (PDOs), we confirmed that OSMI-1 inhibits L-iCCA cell proliferation and migration by downregulating MUC16. Mechanistically, OSMI-1 suppresses MUC16 expression by disrupting the transcriptional complex formed between OGT and IRF1. Employing a genetically engineered L-iCCA mouse model, we further validated the crucial role of MUC16 in tumor progression and neutrophil infiltration, demonstrated that OSMI-1 synergized with gemcitabine, effectively inhibiting L-iCCA growth. This study presents a pathological subtype-based precision therapeutic strategy for L-iCCA, thereby providing a foundation for novel translational approaches to the personalized management of this disease.