O‑GlcNAcylation as an emerging molecular target for cholangiocarcinoma therapy (Review).

Aberrant O‑GlcNAcylation and the upregulation of O‑GlcNAc transferase (OGT) are key contributors to cancer pathogenesis and progression, driving hyperproliferative states and metastatic phenotypes. Targeting OGT may suppress cancer progression, positioning OGT and O‑GlcNAc signaling as compelling targets in cancer research. Cholangiocarcinoma (CCA), a rare yet highly aggressive malignancy of the bile duct system, represents a clinical challenge, underscored by its rising global mortality, poor survival outcomes and high recurrence rate, despite advances in awareness, diagnostics and therapeutic strategies. Consequently, there is need for novel therapeutic modalities. Hyperactive O‑GlcNAcylation and upregulation of OGT are observed in CCA, therefore, targeting protein O‑GlcNAcylation may have clinical potential. The present review aimed to summarize the impact of O‑GlcNAcylation on CCA and CCA‑relevant hallmarks of cancer including cell proliferation, metastasis, metabolic reprogramming, angiogenesis, programmed cell death and tumor‑associated inflammation. In areas where direct evidence in CCA is limited, insights from other gastrointestinal tract cancers may identify potential mechanistic connections, offering a broader context to guide future investigation. Furthermore, the viability of OGT and O‑GlcNAcylation as therapeutic targets is discussed.