Is nicotinamide adenine dinucleotide the Achilles’ heel of chronic interleukin-6 signaling in cholangiocarcinoma?
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Magdalena Hahn1,2
1Institute for Interdisciplinary Research on Cancer, Metabolism and Chronic Inflammation, University of Tübingen, Faculty of Medicine, M3 Research Center for Malignome, Metabolome and Microbiome, Tübingen 72076, Germany.
2Division of Hepatology, Medical Clinic II, Leipzig University Medical Center, Leipzig 04103, Germany.
3Cluster of Excellence iFIT (EXC 2180), “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72074, Germany.
4Cluster of Excellence EXC 2124, “Controlling Microbes to Fight Infections”, University of Tübingen, Tübingen 72074, Germany.
Magdalena Hahn1,2
,
René Tykwe1,3
1Institute for Interdisciplinary Research on Cancer, Metabolism and Chronic Inflammation, University of Tübingen, Faculty of Medicine, M3 Research Center for Malignome, Metabolome and Microbiome, Tübingen 72076, Germany.
2Division of Hepatology, Medical Clinic II, Leipzig University Medical Center, Leipzig 04103, Germany.
3Cluster of Excellence iFIT (EXC 2180), “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72074, Germany.
4Cluster of Excellence EXC 2124, “Controlling Microbes to Fight Infections”, University of Tübingen, Tübingen 72074, Germany.
René Tykwe1,3
,
Mathias Heikenwälder1,3,4
1Institute for Interdisciplinary Research on Cancer, Metabolism and Chronic Inflammation, University of Tübingen, Faculty of Medicine, M3 Research Center for Malignome, Metabolome and Microbiome, Tübingen 72076, Germany.
2Division of Hepatology, Medical Clinic II, Leipzig University Medical Center, Leipzig 04103, Germany.
3Cluster of Excellence iFIT (EXC 2180), “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72074, Germany.
4Cluster of Excellence EXC 2124, “Controlling Microbes to Fight Infections”, University of Tübingen, Tübingen 72074, Germany.
1Institute for Interdisciplinary Research on Cancer, Metabolism and Chronic Inflammation, University of Tübingen, Faculty of Medicine, M3 Research Center for Malignome, Metabolome and Microbiome, Tübingen 72076, Germany.
2Division of Hepatology, Medical Clinic II, Leipzig University Medical Center, Leipzig 04103, Germany.
3Cluster of Excellence iFIT (EXC 2180), “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72074, Germany.
4Cluster of Excellence EXC 2124, “Controlling Microbes to Fight Infections”, University of Tübingen, Tübingen 72074, Germany.
Correspondence to: Prof. Mathias Heikenwälder, Institute for Interdisciplinary Research on Cancer, Metabolism and Chronic Inflammation, University of Tübingen, Faculty of Medicine, M3 Research Center for Malignome, Metabolome and Microbiome, Tübingen 72076, Germany. E-mail: [email protected]
Received: 30 Jun 2026 | First Decision: 21 Jul 2026 | Revised: 14 Aug 2026 | Accepted: 28 Aug 2026 | Published: 8 Sep 2026
Academic Editor: Matteo Donadon | Copy Editor: Ting-Ting Hu | Production Editor: Ting-Ting Hu
1. Gehl V, O'Rourke CJ, Cornillet M, et al. Molecular and cellular consequences of tumour-autonomous IL-6 signalling in intrahepatic cholangiocarcinoma. Gut. 2026;Epub ahead of print.
2. Banales JM, Rodrigues PM, Affò S, et al. ; International CCA Consensus Consortium. Cholangiocarcinoma 2026: status quo, unmet needs and priorities. Nat Rev Gastroenterol Hepatol. 2026;23:65-96.
3. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of extrahepatic cholangiocarcinoma. J Hepatol. 2025;83:211-38.
4. Høgdall D, O’Rourke CJ, Dehlendorff C, et al. Serum IL6 as a prognostic biomarker and IL6R as a therapeutic target in biliary tract cancers. Clin Cancer Res. 2020;26:5655-67.
5. Zhang M, Yang H, Wan L, et al. Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. J Hepatol. 2020;73:1118-30.
6. Garten A, Schuster S, Penke M, Gorski T, de Giorgis T, Kiess W. Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nat Rev Endocrinol. 2015;11:535-46.
7. Wei Y, Xiang H, Zhang W. Review of various NAMPT inhibitors for the treatment of cancer. Front Pharmacol. 2022;13:970553.
8. Ramsey KM, Yoshino J, Brace CS, et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science. 2009;324:651-4.
9. Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science. 2009;324:654-7.
10. Dang CV. A time for MYC: metabolism and therapy. Cold Spring Harb Symp Quant Biol. 2016;81:79-83.
11. Steffeck AWT, Cordova AA, Abdulkadir SA. MAX in cancer: dynamic role of MYC's partner-in-crime. Trends Cancer. 2026;12:217-20.
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Is nicotinamide adenine dinucleotide the Achilles’ heel of chronic interleukin-6 signaling in cholangiocarcinoma?
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