Glucose Addiction in Cholangiocarcinoma: Hepatoma Research, 2025

Introduction

Cholangiocarcinoma (CCA) is the second most common primary liver cancer and is associated with poor prognosis due to late diagnosis and aggressive tumour biology. Increasing evidence links diabetes mellitus and chronic hyperglycemia with both the development and progression of CCA. Tumour cells demonstrate a strong dependence on glucose metabolism—a phenomenon termed “glucose addiction.”

CCA cells frequently upregulate glucose transporters (GLUTs) and glycolytic enzymes, allowing them to utilise glucose for rapid energy generation through aerobic glycolysis (Warburg effect). Beyond energy production, glucose also fuels multiple biosynthetic and signalling pathways that support tumour proliferation, invasion, and resistance to therapy.

Summary

This review highlights how high glucose environments promote cholangiocarcinoma progression through metabolic and signalling mechanisms.

Key mechanisms include:

Enhanced glycolysis (Warburg effect):

Upregulation of GLUT1, PKM2, HK2, PFK1, and LDHA increases glucose uptake and glycolytic flux, supporting rapid tumour growth.

Activation of oncogenic pathways:

Hyperglycemia stimulates signaling cascades such as PI3K–AKT–mTOR, HIF-1α, and MYC, which further drive tumor proliferation and metabolic reprogramming.

Alternative glucose pathways:

Glucose metabolites feed into the pentose phosphate pathway (PPP) and hexosamine biosynthetic pathway (HBP), generating nucleotides, lipids, and glycosylated proteins essential for cancer progression.

Tumor microenvironment changes:

Increased lactate production leads to acidic microenvironments, enhancing tumor invasion and immune evasion.

Importantly, this metabolic dependency may represent an Achilles’ heel of CCA cells. Targeting glucose metabolism—through glycolytic inhibitors, GLUT blockade, or metabolic pathway inhibitors—offers promising therapeutic opportunities for future CCA treatment strategies.