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September 10, 2025Open Access

Glucose metabolic dysregulation and oxidative stress in cholangiocarcinoma: molecular mechanisms, oncogenic drivers, and novel therapeutic targets

MCMakamas ChandaSiriraj Hospital CMChanya Mekasuwandumrong KWKittikorn Tommy WilasrusmeeSiriraj Hospital

Key Points

Targeting metabolic vulnerabilities in cholangiocarcinoma shows promise for therapeutic interventions.
Key oncogenic mutations like KRAS and TP53 are linked to altered glucose metabolism and oxidative stress.
Targeting glycolytic enzymes and utilizing antidiabetic drugs may enhance treatment efficacy in cholangiocarcinoma.
Challenges such as tumor heterogeneity and resistance mechanisms complicate effective clinical translation.

Abstract

Cholangiocarcinoma (CCA) is an aggressive malignancy marked by profound glucose metabolic dysregulation and oxidative stress. Central to this reprogramming is the upregulation of glucose transporters such as GLUT1, driving enhanced glycolytic flux, activation of the pentose phosphate pathway (PPP), increased lactate production, and alterations in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). These metabolic shifts support tumor proliferation, redox balance, and stemness, and are closely linked to recurrent oncogenic mutations, including KRAS, TP53, IDH1/2, ARID1A, FGFR2, and HER2. These mutations converge on key signaling networks that promote metabolic plasticity and therapeutic resistance. Recent evidence suggests that targeting metabolic vulnerabilities offers promising avenues for intervention. Inhibitors of glycolytic enzymes (HKII, PKM2), PPP regulators (G6PD, TKT), TCA cycle components IDH, glutaminase (GLS), lactate metabolism (LDHA), and OXPHOS machinery (Complex I) have demonstrated potential in preclinical models. Additionally, repurposing antidiabetic drugs such as metformin and SGLT2 inhibitors may offer novel metabolic therapies. Regulatory non-coding RNAs, including microRNAs and long non-coding RNAs, further modulate key enzymes and transporters, highlighting their emerging roles as both biomarkers and therapeutic targets. However, challenges such as tumor heterogeneity, metabolic redundancy, off-target toxicity, and resistance mechanisms continue to hinder clinical translation. Integrated therapeutic approaches combining metabolic inhibitors with chemotherapy, immunotherapy, or targeted agents are likely necessary to overcome these barriers. This review synthesizes the current understanding of glucose metabolism and redox dysregulation in CCA, emphasizing the molecular drivers, therapeutic opportunities, and translational challenges, with the goal of guiding future research toward more effective and personalized treatment strategies.

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