Ferroptosis in Cholangiocarcinoma Therapy: Molecular Mechanisms, Pharmacological Modulation and Opportunities for Drug Development
Athar H. Zulfiqar S. Ali A. Armaghan M. Khan K. Setzer W.N. Sharifi-Rad J. Calina D.
April 2026John Wiley and Sons Inc
Drug Development Research
2026#87Issue 2
Cholangiocarcinoma (CCA) is a type of cancer that has a rather high mortality rate and arises from cholangiocytes. Due to its aggressive nature, CCA is considered a rare and highly advanced form of malignancy. This research is detailed around which role does ferroptosis play in CCA and what impact does it have on CCA progression as well as on treatment resistance. A systematic assessment of previously published works was conducted to understand the cellular mechanisms of ferroptosis, the pertinent biological networks, and its possible therapeutic targets. During the research, we discovered that the sensitivity of CCA cells to ferroptosis associated cell death is increased because they have dysregulated iron metabolism and uncontrolled lipid peroxidation. Sensitivity to ferroptosis is regulated by important proteins such as acyl-CoA synthetase long-chain family member 4 (ACSL4) and solute carrier family 7 member 11 (SLC7A11). In addition, the ferroptosis inducers erastin and RSL3 are capable of enhancing the efficacy of traditional therapies and seeking solutions for the chemoresistance problem. The hurdles to be overcome are finding reliable biomarkers for the prediction of ferroptosis sensitivity and designing targeted delivery systems for minimal off-target effects. Clinically, these techniques offer novel concepts in the treatment of CCA, making further research key to these conclusions being adopted in practice.
ACSL4 , chemoresistance , cholangiocarcinoma , ferroptosis , SLC7A11 , therapeutic strategy
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National University of Science and Technology (NUST), Islamabad, Pakistan
School of Medicine (NUSOM), Nazarbayev University, Astana, Kazakhstan
Clinical and Preclinical Studies Unit, Lahore, Pakistan
Aromatic Plant Research Center, Lehi, UT, United States
Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL, United States
Universidad Espíritu Santo, Samborondón, Ecuador
Department of Medicine, College of Medicine, Korea University, Seoul, South Korea
Centro de Estudios Tecnológicos y Universitarios del Golfo, Veracruz, Mexico
Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, Romania
National University of Science and Technology (NUST)
School of Medicine (NUSOM)
Clinical and Preclinical Studies Unit
Aromatic Plant Research Center
Department of Chemistry
Universidad Espíritu Santo
Department of Medicine
Centro de Estudios Tecnológicos y Universitarios del Golfo
Department of Clinical Pharmacy
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